Heterocycle amines and uses thereof

ABSTRACT

Compounds and methods in the fields of chemistry and medicine are disclosed. Some of the disclosed embodiments include compounds, compositions and methods of using heterocycle amines. Some of the disclosed embodiments include heterocycle amines useful to treat inflammatory disorders.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/006,940 filed Jan. 26, 2016 which is a continuation of U.S.application Ser. No. 14/137,318 filed Dec. 20, 2013 now U.S. Pat. No.9,266,874 which issued Feb. 23, 2016 which is a continuation of U.S.application Ser. No. 13/885,138 filed May 13, 2013 now abandoned whichis the U.S. National Phase of Application No. PCT/US2011/061532 entitled“HETEROCYCLE AMINES AND USES THEREOF” filed Nov. 18, 2011 and publishedin English on May 24, 2012 as WO2012/068546 which claims the benefit ofU.S. Provisional Application No. 61/415,685 filed Nov. 19, 2010 entitled“HETEROCYCLE AMINES AND USES THEREOF” which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

Compounds and methods in the fields of chemistry and medicine aredisclosed. Some of the disclosed embodiments include compounds,compositions and methods of using heterocycle amines. Some of thedisclosed embodiments include heterocycle amines useful to treatinflammatory disorders.

BACKGROUND

The recruitment of immune cells to sites of injury involves theconcerted interactions of a large number of soluble mediators. Severalcytokines appear to play roles in these processes, for example, IL-1 andTNF. Both cytokines are derived from mononuclear cells and macrophagesalong with other cell types. Physiologically, they produce many of thesame proinflammatory responses, including fever, sleep, anorexia,mobilization and activation of polymorphonuclear leukocytes, inductionof cyclooxygenase and lipoxygenase enzymes, increase in adhesionmolecule expression, activation of B-cells, T-cells and natural killercells, and stimulation of production of other cytokines. Other actionsinclude a contribution to the tissue degeneration seen in chronicinflammatory conditions, such as stimulation of fibroblastproliferation, induction of collagenase, etc. They have also beenimplicated in the process of bone resorption and adipose tissueregulation. Thus, these cytokines play key roles in a large number ofpathological conditions, including rheumatoid arthritis, inflammatorybowel disease, multiple sclerosis, diabetes, obesity, cancer, andsepsis.

The role of IL-1 in inflammation has been demonstrated by the ability ofthe highly specific IL-1 receptor antagonist protein (IL-1 Ra, or IRAP)to relieve inflammatory conditions. IL-1 treatment of cells induces theformation of a complex consisting of the two IL-1 receptor chains,IL-IRI and IL-1 RAcP, and the resulting heterodimer recruits an adaptormolecule designated as MyD88. MyD88 binds to a protein designated IRAK(Interleukin-1 Receptor-Associated Kinase). IRAK is subsequentlyphosphorylated and released from the receptor complex to interact with atumor necrosis factor receptor-associated factor, TRAF6, whichtransduces the signal to downstream effector molecules. TRAF6 cantrigger the NIK/IKK kinase cascade to activate the transcription factorNF-κB. NF-κB regulates a number of genes that, in turn, regulate immuneand inflammatory responses.

Four IRAKs have been identified: IRAK-1, IRAK-2, the monomyeloiccell-specific IRAK-M, also known as IRAK-3, and IRAK-4. IRAK proteinshave been shown to play a role in transducing signals other than thoseoriginating from IL-I receptors, including signals triggered byactivation of IL-18 receptors and LPS receptors. Overexpression ofIRAK-2 and IRAK-M has been shown to be capable of reconstituting theresponse to IL-1 and LPS in an IRAK deficient cell line.

SUMMARY OF THE INVENTION

Compounds, compositions and methods of using heterocycle amines aredisclosed. Some of the disclosed embodiments include heterocycle aminesuseful to treat inflammatory disorders.

Some embodiments include a compound of Formula (I):

-   -   or a salt, ester, amide, or prodrug thereof,    -   wherein    -   is a single or double bond;    -   W is selected from CH, CH—CH, O, S, NR⁶, and CO;    -   Y is N or CR⁹;    -   Z is N or C, and Z is N if W is CH and Y is CR⁹;    -   R⁴ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        an optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted non-aromatic ring, an        optionally substituted carbocycle, an optionally substituted        C₁-C₆ alkyl, an optionally substituted C₁-C₆ haloalkyl, an        optionally substituted C₁-C₆ heteroalkyl, an optionally        substituted C₁-C₆ alkenyl, an optionally substituted C₁-C₆        alkynyl, CO₂R⁶, SO₃R⁶, SO₂R⁶ and SO₂NR⁷R⁸;    -   R⁵ is selected from hydrogen, halogen, OR⁶, an optionally        substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆        haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an        optionally substituted C₁-C₆ haloheteroalkyl, an optionally        substituted C₁-C₆ alkenyl, and an optionally substituted C₁-C₆        alkynyl;    -   or R⁴ and R⁵ are linked to form an optionally substituted        non-aromatic ring;    -   each R⁶ is independently selected from an optionally substituted        aryl, an optionally substituted heteroaryl, and an optionally        substituted non-aromatic ring, each optionally fused with a        substituted aryl or a substituted heteroaryl, hydrogen, an        optionally substituted C₁-C₁₀ alkyl, an optionally substituted        C₁-C₁₀ haloalkyl, and an optionally substituted C₁-C₁₀        heteroalkyl;    -   each R⁷ and R⁸ is independently selected from an optionally        substituted aryl, an optionally substituted heteroaryl, an        optionally substituted non-aromatic ring, each optionally fused        with a substituted aryl or a substituted heteroaryl, hydrogen,        an optionally substituted C₁-C₁₀ alkyl, an optionally        substituted C₁-C₁₀ haloalkyl, an optionally substituted C₁-C₁₀        alkenyl, an optionally substituted C₁-C₁₀ alkynyl, and an        optionally substituted C₁-C₁₀ heteroalkyl, or R⁷ and R⁸ are        linked to form an optionally substituted non-aromatic ring;    -   R⁹ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        an optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted non-aromatic ring, an        optionally substituted C₁-C₆ alkyl, an optionally substituted        C₁-C₆ haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an        optionally substituted C₁-C₆ alkenyl, an optionally substituted        C₁-C₆ alkynyl, CO₂R⁶, SO₃R⁶, and SO₂NR⁷R⁸;    -   A is an optionally substituted aryl or an optionally substituted        heteroaryl group;    -   each optionally substituted group is either unsubstituted or        substituted with one or more groups independently selected from        alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl,        heterohaloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic ring,        hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano,        halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,        O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,        N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,        isothiocyanato, nitro, silyl, trihalomethanesulfonyl, ═O, ═S,        amino, and protected derivatives of amino groups.

In some embodiments, R⁴ is selected from hydrogen, halogen, OR⁶, CN,NR⁷R⁸, CH₂OR⁶, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted non-aromatic ring, an optionallysubstituted carbocycle, an optionally substituted C₁-C₆ alkyl, anoptionally substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆heteroalkyl, an optionally substituted C₁-C₆ alkenyl, an optionallysubstituted C₁-C₆ alkynyl, CO₂R⁶, SO₃R⁶, SO₂R⁶ and SO₂NR⁷R⁸.

In some embodiments, if R⁴ is pyrazolyl, the pyrazolyl is notsubstituted with aryl or heteroaryl groups.

In some embodiments, if R⁴ is oxazolyl, isoxazolyl, or imidazoyl, theoxazolyl, isoxazolyl, or imidazoyl radical is not substituted with arylor heteroaryl groups.

Some embodiments include a compound represented by Formula (I-A):

-   -   or a salt, ester, amide, or prodrug thereof,    -   wherein    -   X is N or CR⁵′, wherein R⁵′ is selected from hydrogen, halogen,        OR⁶, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        heteroalkyl, an optionally substituted C₁-C₆ haloheteroalkyl, an        optionally substituted C₁-C₆ alkenyl, and an optionally        substituted C₁-C₆ alkynyl;    -   R¹ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        CH₂NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        alkenyl, an optionally substituted C₁-C₆ alkynyl, an optionally        substituted C₁-C₆ heteroalkyl, CO₂R⁶, CONR⁷R⁸, SO₃R⁶, and        SO₂NR⁷R⁸;    -   R² and R³ are independently selected from hydrogen, halogen,        OR⁶, NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        alkenyl, an optionally substituted C₁-C₆ alkynyl, and an        optionally substituted C₁-C₆ heteroalkyl.

Some embodiments include a compound represented by Formula (II):

-   -   or a salt, ester, amide, or prodrug thereof.

Some embodiments include a compound represented by Formula (III):

-   -   or a salt, ester, amide, or prodrug thereof,    -   wherein    -   X is N or CR⁵′, wherein R⁵′ is selected from hydrogen, halogen,        OR⁶, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        heteroalkyl, an optionally substituted C₁-C₆ haloheteroalkyl, an        optionally substituted C₁-C₆ alkenyl, and an optionally        substituted C₁-C₆ alkynyl;    -   R¹ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        CH₂NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        alkenyl, an optionally substituted C₁-C₆ alkynyl, an optionally        substituted C₁-C₆ heteroalkyl, CO₂R⁶, CONR⁷R⁸, SO₃R⁶, and        SO₂NR⁷R⁸;    -   R² and R³ are independently selected from hydrogen, halogen,        OR⁶, NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        alkenyl, an optionally substituted C₁-C₆ alkynyl, and an        optionally substituted C₁-C₆ heteroalkyl.

In some embodiments, W is S.

In some embodiments, X is N.

In some embodiments, Y is CR⁹.

In some embodiments, R⁴ is selected from the group consisting ofpyridyl, pyrazolyl, cyano, triazolyl, and oxazolyl.

In some embodiments, Y is N.

In some embodiments, R⁴ is selected from the group consisting ofpyridyl, pyrazolyl, pyrimidinyl, pyridazinyl, and C₁-C₆ alkyl.

Some embodiments include a compound represented by Formula (IV):

-   -   or a salt, ester, amide, or prodrug thereof,    -   wherein:    -   X is N or CR⁵′, wherein R⁵′ is selected from hydrogen, halogen,        OR⁶, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        heteroalkyl, an optionally substituted C₁-C₆ haloheteroalkyl, an        optionally substituted C₁-C₆ alkenyl, and an optionally        substituted C₁-C₆ alkynyl;    -   R¹ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        CH₂NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        alkenyl, an optionally substituted C₁-C₆ alkynyl, an optionally        substituted C₁-C₆ heteroalkyl, CO₂R⁶, CONR⁷R⁸, SO₃R⁶, and        SO₂NR⁷R⁸; and    -   R² and R³ are independently selected from hydrogen, halogen,        OR⁶, NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        alkenyl, an optionally substituted C₁-C₆ alkynyl, and an        optionally substituted C₁-C₆ heteroalkyl.

In some embodiments, X is N.

Some embodiments include a pharmaceutical composition comprising acompound provided herein and a pharmaceutically acceptable carrier.

Some embodiments include a method of treating a disorder responsive toinhibition of Interleukin-1 Receptor-Associated Kinase-mediated signaltransduction comprising administering to a subject in need thereof aneffective amount of a compound provided herein.

In some embodiments, the disorder is an inflammatory disorder. In someembodiments, the inflammatory disorder is selected from the groupconsisting of osteoarthritis, rheumatoid arthritis, multiple sclerosis,corneal ulcers, uveitis, and inflammatory bowel disease.

In some embodiments, the disorder is a skin disorder. In someembodiments, the skin disorder is selected from the group consisting ofdermatitis, cutaneous eosinophilias, Lichen planus, urticaria,psoriasis, pruritus, angioedemas, chronic skin ulcers, conjunctivitis,vasculitides, and erythemas.

In some embodiments, the disorder is a respiratory disorder. In someembodiments, the respiratory disorder is selected from the groupconsisting of asthma, rhinitis, chronic obstructive pulmonary disease,bronchitis, nasal polyposis, nasal congestion, farmer's lung, fibroidlung and cough.

In some embodiments, the disorder is selected from the group consistingof diabetes, obesity, allergic disease, cancer, and sepsis.

Some embodiments include use of a compound provided herein in thepreparation of a medicament for treating a disorder responsive toinhibition of Interleukin-1 Receptor-Associated Kinase-mediated signaltransduction.

In some embodiments, the disorder is an inflammatory disorder. In someembodiments, the inflammatory disorder is selected from the groupconsisting of osteoarthritis, rheumatoid arthritis, multiple sclerosis,corneal ulcers, uveitis, and inflammatory bowel disease.

In some embodiments, the disorder is a skin disorder. In someembodiments, the skin disorder is selected from the group consisting ofdermatitis, cutaneous eosinophilias, Lichen planus, urticaria,psoriasis, pruritus, angioedemas, chronic skin ulcers, conjunctivitis,vasculitides, and erythemas.

In some embodiments, the disorder is a respiratory disorder. In someembodiments, the respiratory disorder is selected from the groupconsisting of asthma, rhinitis, chronic obstructive pulmonary disease,bronchitis, nasal polyposis, nasal congestion, farmer's lung, fibroidlung and cough.

In some embodiments, the disorder is selected from the group consistingof diabetes, obesity, allergic disease, cancer, and sepsis.

Some embodiments include a compound provided herein for treating adisorder responsive to inhibition of Interleukin-1 Receptor-AssociatedKinase-mediated signal transduction.

In some embodiments, the disorder is an inflammatory disorder. In someembodiments, the inflammatory disorder is selected from the groupconsisting of osteoarthritis, rheumatoid arthritis, multiple sclerosis,corneal ulcers, uveitis, and inflammatory bowel disease.

In some embodiments, the disorder is a skin disorder. In someembodiments, the skin disorder is selected from the group consisting ofdermatitis, cutaneous eosinophilias, Lichen planus, urticaria,psoriasis, pruritus, angioedemas, chronic skin ulcers, conjunctivitis,vasculitides, and erythemas.

In some embodiments, the disorder is a respiratory disorder. In someembodiments, the respiratory disorder is selected from the groupconsisting of asthma, rhinitis, chronic obstructive pulmonary disease,bronchitis, nasal polyposis, nasal congestion, farmer's lung, fibroidlung and cough.

In some embodiments, the disorder is selected from the group consistingof diabetes, obesity, allergic disease, cancer, and sepsis.

DETAILED DESCRIPTION

Compounds and methods in the fields of chemistry and medicine aredisclosed. Some of the disclosed embodiments include compounds,compositions and methods of using heterocycle amines. Some of thedisclosed embodiments include heterocycle amines useful to treatinflammatory disorders.

Some embodiments include a compound of Formula (I):

-   -   or a salt, ester, amide, or prodrug thereof,    -   wherein    -   is a single or double bond;    -   W is selected from CH, CH—CH, O, S, NR⁶, and CO;    -   Y is N or CR⁹;    -   Z is N or C, and Z is N if W is CH and Y is CR⁹;    -   R⁴ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        an optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted non-aromatic ring, an        optionally substituted carbocycle, an optionally substituted        C₁-C₆ alkyl, an optionally substituted C₁-C₆ haloalkyl, an        optionally substituted C₁-C₆ heteroalkyl, an optionally        substituted C₁-C₆ alkenyl, an optionally substituted C₁-C₆        alkynyl, CO₂R⁶, SO₃R⁶, SO₂R⁶ and SO₂NR⁷R⁸;    -   R⁵ is selected from hydrogen, halogen, OR⁶, an optionally        substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆        haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an        optionally substituted C₁-C₆ haloheteroalkyl, an optionally        substituted C₁-C₆ alkenyl, and an optionally substituted C₁-C₆        alkynyl;    -   or R⁴ and R⁵ are linked to form an optionally substituted        non-aromatic ring;    -   each R⁶ is independently selected from an optionally substituted        aryl, an optionally substituted heteroaryl, and an optionally        substituted non-aromatic ring, each optionally fused with a        substituted aryl or a substituted heteroaryl, hydrogen, an        optionally substituted C₁-C₁₀ alkyl, an optionally substituted        C₁-C₁₀ haloalkyl, and an optionally substituted C₁-C₁₀        heteroalkyl;    -   each R⁷ and R⁸ is independently selected from an optionally        substituted aryl, an optionally substituted heteroaryl, an        optionally substituted non-aromatic ring, each optionally fused        with a substituted aryl or a substituted heteroaryl, hydrogen,        an optionally substituted C₁-C₁₀ alkyl, an optionally        substituted C₁-C₁₀ haloalkyl, an optionally substituted C₁-C₁₀        alkenyl, an optionally substituted C₁-C₁₀ alkynyl, and an        optionally substituted C₁-C₁₀ heteroalkyl, or R⁷ and R⁸ are        linked to form an optionally substituted non-aromatic ring;    -   R⁹ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        an optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted non-aromatic ring, an        optionally substituted C₁-C₆ alkyl, an optionally substituted        C₁-C₆ haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an        optionally substituted C₁-C₆ alkenyl, an optionally substituted        C₁-C₆ alkynyl, CO₂R⁶, SO₃R⁶, and SO₂NR⁷R⁸;    -   A is an optionally substituted aryl or an optionally substituted        heteroaryl group;    -   each optionally substituted group is either unsubstituted or        substituted with one or more groups independently selected from        alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl,        heterohaloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic ring,        hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano,        halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,        O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,        N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,        isothiocyanato, nitro, silyl, trihalomethanesulfonyl, ═O, ═S,        amino, and protected derivatives of amino groups.

In some embodiments, R⁴ is selected from hydrogen, halogen, OR⁶, CN,NR⁷R⁸, CH₂OR⁶, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted non-aromatic ring, an optionallysubstituted carbocycle, an optionally substituted C₁-C₆ alkyl, anoptionally substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆heteroalkyl, an optionally substituted C₁-C₆ alkenyl, an optionallysubstituted C₁-C₆ alkynyl, CO₂R⁶, SO₃R⁶, SO₂R⁶ and SO₂NR⁷R⁸.

In some embodiments, if R⁴ is pyrazolyl, the pyrazolyl is notsubstituted with aryl or heteroaryl groups.

In some embodiments, if R⁴ is oxazolyl, isoxazolyl, or imidazoyl, theoxazolyl, isoxazolyl, or imidazoyl radical is not substituted with arylor heteroaryl groups.

Some embodiments include a compound represented by Formula (I-A):

-   -   or a salt, ester, amide, or prodrug thereof,    -   wherein    -   X is N or CR⁵′, wherein R⁵′ is selected from hydrogen, halogen,        OR⁶, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        heteroalkyl, an optionally substituted C₁-C₆ haloheteroalkyl, an        optionally substituted C₁-C₆ alkenyl, and an optionally        substituted C₁-C₆ alkynyl;    -   R¹ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        CH₂NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        alkenyl, an optionally substituted C₁-C₆ alkynyl, an optionally        substituted C₁-C₆ heteroalkyl, CO₂R⁶, CONR⁷R⁸, SO₃R⁶, and        SO₂NR⁷R⁸;    -   R² and R³ are independently selected from hydrogen, halogen,        OR⁶, NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        alkenyl, an optionally substituted C₁-C₆ alkynyl, and an        optionally substituted C₁-C₆ heteroalkyl.

Some embodiments include a compound represented by Formula (II):

-   -   or a salt, ester, amide, or prodrug thereof.

Some embodiments include a compound represented by Formula (III):

-   -   or a salt, ester, amide, or prodrug thereof,    -   wherein    -   X is N or CR⁵′, wherein R⁵′ is selected from hydrogen, halogen,        OR⁶, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        heteroalkyl, an optionally substituted C₁-C₆ haloheteroalkyl, an        optionally substituted C₁-C₆ alkenyl, and an optionally        substituted C₁-C₆ alkynyl;    -   R¹ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        CH₂NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        alkenyl, an optionally substituted C₁-C₆ alkynyl, an optionally        substituted C₁-C₆ heteroalkyl, CO₂R⁶, CONR⁷R⁸, SO₃R⁶, and        SO₂NR⁷R⁸;    -   R² and R³ are independently selected from hydrogen, halogen,        OR⁶, NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        alkenyl, an optionally substituted C₁-C₆ alkynyl, and an        optionally substituted C₁-C₆ heteroalkyl.

In some embodiments, W is S.

In some embodiments, X is N.

In some embodiments, Y is CR⁹.

In some embodiments, R⁴ is selected from the group consisting ofpyridyl, pyrazolyl, cyano, triazolyl, and oxazolyl.

In some embodiments, Y is N.

In some embodiments, R⁴ is selected from the group consisting ofpyridyl, pyrazolyl, pyrimidinyl, pyridazinyl, and C₁-C₆ alkyl.

Some embodiments include a compound represented by Formula (IV):

-   -   or a salt, ester, amide, or prodrug thereof,    -   wherein:    -   X is N or CR⁵′, wherein R⁵′ is selected from hydrogen, halogen,        OR⁶, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        heteroalkyl, an optionally substituted C₁-C₆ haloheteroalkyl, an        optionally substituted C₁-C₆ alkenyl, and an optionally        substituted C₁-C₆ alkynyl;    -   R¹ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        CH₂NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        alkenyl, an optionally substituted C₁-C₆ alkynyl, an optionally        substituted C₁-C₆ heteroalkyl, CO₂R⁶, CONR⁷R⁸, SO₃R⁶, and        SO₂NR⁷R⁸; and    -   R² and R³ are independently selected from hydrogen, halogen,        OR⁶, NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        alkenyl, an optionally substituted C₁-C₆ alkynyl, and an        optionally substituted C₁-C₆ heteroalkyl.

In some embodiments, X is N.

Definitions

Unless specific definitions are provided, the nomenclatures utilized inconnection with, and the laboratory procedures and techniques of,analytical chemistry, synthetic organic chemistry, and medicinal andpharmaceutical chemistry described herein are those known in the art.Standard chemical symbols are used interchangeably with the full namesrepresented by such symbols. Thus, for example, the terms “hydrogen” and“H” are understood to have identical meaning. Standard techniques may beused for chemical syntheses, chemical analyses, pharmaceuticalpreparation, formulation, and delivery, and treatment of patients.Standard techniques may be used for recombinant DNA, oligonucleotidesynthesis, and tissue culture and transformation (e.g., electroporation,lipofection). Reactions and purification techniques may be performede.g., using kits according to manufacturer's specifications or ascommonly accomplished in the art or as described herein. The foregoingtechniques and procedures may be generally performed according toconventional methods well known in the art and as described in variousgeneral and more specific references that are cited and discussedthroughout the present specification. See e.g., Sambrook et al.Molecular Cloning: A Laboratory Manual (2^(nd) ed., Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y. (1989)), which isincorporated herein by reference in its entirety for any purpose.

The term “alkyl” refers to a branched or unbranched aliphatichydrocarbon group. An alkyl may be a “saturated alkyl,” which means thatit does not contain any alkene or alkyne groups. An alkyl group may bean “unsaturated alkyl,” which means that it comprises at least onealkene or alkyne group. An alkyl, whether saturated or unsaturated, maybe branched or straight chain. Alkyls may be cyclic or non-cyclic.Cyclic alkyls may include multicyclic systems including fused alkylrings. Alkyls may be substituted or unsubstituted. Alkyls include, butare not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like, each of which may beoptionally substituted.

In certain embodiments, an alkyl comprises 1 to 20 carbon atoms(whenever it appears herein, a numerical range such as “1 to 20” refersto each integer in the given range; e.g., “1 to 20 carbon atoms” meansthat an alkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 20 carbon atoms, although theterm “alkyl” also includes instances where no numerical range of carbonatoms is designated).

The term “lower alkyl” refers to an alkyl comprising 1 to 5 carbonatoms. The term “medium alkyl” refers to an alkyl comprising 5 to 10carbon atoms. An alkyl may be designated as “C₁-C₄ alkyl” or similardesignations. By way of example only, “C₁-C₄ alkyl” indicates an alkylhaving one, two, three, or four carbon atoms, e.g., the alkyl isselected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, and t-butyl.

The term “alkenyl” refers to an alkyl group comprising at least onecarbon-carbon double bond, including by way of non-limiting exampleethenyl, propenyl, and butenyl.

The term “alkynyl” refers to an alkyl group comprising at least onecarbon-carbon triple bond, including by way of non-limiting exampleethynyl, propynyl, and butynyl.

The term “haloalkyl” refers to an alkyl in which at least one hydrogenatom is replaced with a halogen atom. In certain of the embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are all the same as one another. In certain of suchembodiments, the halogen atoms are not all the same as one another.

The term “heteroalkyl” refers to a branched or unbranched aliphatichydrocarbon group comprising one or more oxygen, sulfur, nitrogen, orNH. Examples of heteroalkyls include, but are not limited to,CH₃C(═O)CH₂—, CH₃C(═O)CH₂CH₂—, CH₃CH₂C(═O)CH₂CH₂—, CH₃C(═O)CH₂CH₂CH₂—,CH₃NHC(═O)CH₂—, CH₃C(═O)NHCH₂—, CH₃OCH₂CH₂—, CH₃NHCH₂—, and the like.

The term “straight-chain alkoxy” refers to a group comprising theformula: —(CH₂)_(p)O— wherein p is any integer. Straight-chain alkoxydoes not include substituted or branched alkoxy groups.

The term “non-straight-chain-alkoxy-heteroalkyl” refers to anyheteroalkyl that is not a straight-chain alkoxy heteroalkyl. Thus, forexample, non-straight-chain-alkoxy heteroalkyls include, but are notlimited to: 2,2-isopropyloxy; 1,2-propyloxy; 1,1-ethyloxy; methylamino;ethylamino; propylamino; methylpyrrolidino; and methylpiperidino.

The term “heterohaloalkyl” refers to a heteroalkyl in which at least onehydrogen atom is replaced with a halogen atom.

The term “carbocycle” refers to a group comprising a covalently closedring, wherein each of the atoms that forms and/or comprises the ring isa carbon atom. Carbocyclic rings may be formed by three, four, five,six, seven, eight, nine, or more than nine carbon atoms. Carbocycles maybe optionally substituted.

The term “heterocycle” refers to a group comprising a covalently closedring wherein at least one atom that forms and/or comprises the ring is aheteroatom. Heterocyclic rings may be formed by three, four, five, six,seven, eight, nine, or more than nine atoms. Any number of those atomsmay be heteroatoms (i.e., a heterocyclic ring may comprise one, two,three, four, five, six, seven, eight, nine, or more than nineheteroatoms). In heterocyclic rings comprising two or more heteroatoms,those two or more heteroatoms may be the same or different from oneanother. Heterocycles may be optionally substituted. Binding to aheterocycle can be at a heteroatom or via a carbon atom. For example,binding for benzo-fused derivatives, may be via a carbon of thebenzenoid ring. Examples of heterocycles include, but are not limited tothe following:

wherein D, E, F, and G independently represent a heteroatom. Each of D,E, F, and G may be the same or different from one another.

The term “heteroatom” refers to an atom other than carbon or hydrogen.Heteroatoms, typically, are independently selected from oxygen, sulfur,nitrogen, and phosphorus, but heteroatoms are not limited to thoseatoms. In embodiments in which two or more heteroatoms are present, thetwo or more heteroatoms may all be the same as one another, or some orall of the two or more heteroatoms may each be different from theothers.

The term “aromatic” refers to a group comprising a covalently closedring having a delocalized π-electron system. Aromatic rings may beformed by five, six, seven, eight, nine, or more than nine atoms.Aromatics may be optionally substituted. Examples of aromatic groupsinclude, but are not limited to phenyl, naphthalenyl, phenanthrenyl,anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl. The termaromatic includes, for example, benzenoid groups, connected via one ofthe ring-forming carbon atoms, and optionally carrying one or moresubstituents selected from an aryl, a heteroaryl, a cycloalkyl, anon-aromatic ring, a halo, a hydroxy, an amino, a cyano, a nitro, analkylamido, an acyl, a C₁₋₆ alkoxy, a C₁₋₆ alkyl, a C₁₋₆ hydroxyalkyl, aC₁₋₆ aminoalkyl, a C₁₋₆ alkylamino, an alkylsulfenyl, an alkylsulfinyl,an alkylsulfonyl, an sulfamoyl, or a trifluoromethyl. In certainembodiments, an aromatic group is substituted at one or more of thepara, meta, and/or ortho positions. Examples of aromatic groupscomprising substitutions include, but are not limited to, phenyl,3-halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl,3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl,3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl,hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl,4-morpholin-4-ylphenyl, 4-pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl,4-triazolylphenyl, and 4-(2-oxopyrrolidin-1-yl)phenyl.

The term “aryl” refers to an aromatic group wherein each of the atomsforming the ring is a carbon atom. Aryl rings may be formed by five,six, seven, eight, nine, or more than nine carbon atoms. Aryl groups maybe optionally substituted.

The term “heteroaryl” refers to an aromatic group wherein at least oneatom forming the aromatic ring is a heteroatom. Heteroaryl rings may beformed by three, four, five, six, seven, eight, nine, or more than nineatoms. Heteroaryl groups may be optionally substituted. Examples ofheteroaryl groups include, but are not limited to, aromatic C₃₋₈heterocyclic groups comprising one oxygen or sulfur atom or up to fournitrogen atoms, or a combination of one oxygen or sulfur atom and up totwo nitrogen atoms, and their substituted as well as benzo- andpyrido-fused derivatives, for example, connected via one of thering-forming carbon atoms. In certain embodiments, heteroaryl groups areoptionally substituted with one or more substituents, independentlyselected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl,C₁₋₆-alkoxy, C₁₋₆-alkyl, C₁₋₆-hydroxyalkyl, C₁₋₆-aminoalkyl,C₁₋₆-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl,or trifluoromethyl. Examples of heteroaryl groups include, but are notlimited to, unsubstituted and mono- or di-substituted derivatives offuran, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole,oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole,isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole,quinoline, isoquinoline, pyridazine, pyrimidine, purine, pyrazine,furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole,triazole, benzotriazole, pteridine, phenoxazole, oxadiazole,benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, andquinoxaline. In some embodiments, the substituents are halo, hydroxy,cyano, 0-C₁₋₆-alkyl, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl, andamino-C₁₋₆-alkyl.

The term “non-aromatic ring” refers to a group comprising a covalentlyclosed ring that does not have a delocalized π-electron system in itsprinciple and/or predominant tautomer.

The term “cycloalkyl” refers to a group comprising a non-aromatic ringwherein each of the atoms forming the ring is a carbon atom. Cycloalkylrings may be formed by three, four, five, six, seven, eight, nine, ormore than nine carbon atoms. Cycloalkyls may include multicyclic systems(e.g., fused ring systems). Cycloalkyls may be optionally substituted.In certain embodiments, a cycloalkyl comprises one or more unsaturatedbonds. Examples of cycloalkyls include, but are not limited to,cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene,cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene,cycloheptane, and cycloheptene.

The term “non-aromatic ring” refers to a group comprising a non-aromaticring moiety wherein the atoms that form and/or comprise the ring includecarbon and/or heteroatoms. When heteroatoms are included in the ring,one or more such heteroatoms may be present. Non-aromatic rings alsooptionally include one or more carbonyl or thiocarbonyl groups as partof the ring. Non-aromatic rings may be formed by three, four, five, six,seven, eight, nine, or more than nine atoms. Non-aromatic rings may beoptionally substituted. Examples of non-aromatic rings include, but arenot limited to, cycloalkyls (including but not limited to cyclopropane,cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane,cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, andcycloheptene), lactams, lactones, cyclic imides, cyclic thioimides,cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran,piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane,piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane,tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline,imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane,isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone,thiazoline, thiazolidine, and 1,3-oxathiolane.

The term “arylalkyl” refers to a group comprising an aryl group bound toan alkyl group.

The term “ring” refers to any covalently closed structure. Ringsinclude, for example, carbocycles (e.g., aryls and cycloalkyls),heterocycles (e.g., heteroaryls and non-aromatic heterocyclic rings),aromatics (e.g., aryls and heteroaryls), and non-aromatic rings. Ringsmay be optionally substituted. Rings may form part of a ring system.

The term “ring system” refers to a either a single ring or two or morerings, wherein, if two or more rings are present, the two or more of therings are fused. The term “fused” refers to structures in which two ormore rings share one or more bonds.

The substituent “R” appearing by itself and without a number designationrefers to a substituent selected from alkyl, cycloalkyl, aryl,heteroaryl (bonded through a ring carbon) and non-aromatic ring (bondedthrough a ring carbon).

The term “O-carboxy” refers to the group consisting of formula RC(═O)O—.

The term “C-carboxy” refers to the group consisting of formula —C(═O)OR.

The term “acetyl” refers to the group consisting of formula —C(═O)CH₃.

The term “trihalomethanesulfonyl” refers to the group consisting offormula X₃CS(═O)₂— where X is a halogen.

The term “cyano” refers to the group consisting of formula —CN.

The term “isocyanato” refers to the group consisting of formula —NCO.

The term “thiocyanato” refers to the group consisting of formula —CNS.

The term “isothiocyanato” refers to the group consisting of formula—NCS.

The term “sulfonyl” refers to the group consisting of formula —S(═O)—R.

The term “S-sulfonamido” refers to the group consisting of formula—S(═O)₂NR.

The term “N-sulfonamido” refers to the group consisting of formulaRS(═O)₂NH—.

The term “trihalomethanesulfonamido” refers to the group consisting offormula X₃CS(═O)₂NR—.

The term “O-carbamyl” refers to the group consisting of formula—OC(═O)—NR.

The term “N-carbamyl” refers to the group consisting of formulaROC(═O)NH—.

The term “O-thiocarbamyl” refers to the group consisting of formula—OC(═S)—NR.

The term “N-thiocarbamyl” refers to the group consisting of formulaROC(═S)NH—.

The term “C-amido” refers to the group consisting of formula —C(═O)—NR₂.

The term “N-amido” refers to the group consisting of formula RC(═O)NH—.

The term “oxo” refers to the group consisting of formula ═O.

The term “carbonyl” refers to the group consisting of formula C(═O)R.

The term “thiocarbonyl” refers to the group consisting of formulaC(═S)R.

The term “dihydropyrazolylene” refers to a di-radical of an optionallysubstituted dihydropyrazole ring, wherein the dihydropyrazole ring hasthe structure:

and wherein the two radicals may be at any positions on the ring.

The term “pyrazolyl” refers to a radical of a pyrazole ring, wherein thepyrazole ring has the structure:

and wherein the radical may be at any position on the ring.

The term “ester” refers to a chemical moiety with formula—(R)_(n)—COOR′, where R and R′ are independently selected from alkyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andnon-aromatic ring (bonded through a ring carbon), where n is 0 or 1.

The term “amide” refers to a chemical moiety with formula—(R)_(n)—C(O)NHR′ or —(R)_(n)—NHC(O)R′, where R and R′ are independentlyselected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ringcarbon) and heteroalicyclic (bonded through a ring carbon), where n is 0or 1. In certain embodiments, an amide may be an amino acid or form partof a peptide.

The terms “amine,” “hydroxy,” and “carboxyl” include such groups thathave been esterified or amidified. Procedures and specific groups usedto achieve esterification and amidification are known to those of skillin the art and can readily be found in reference sources such as Greeneand Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley &Sons, New York, N.Y., 1999, which is incorporated herein in itsentirety.

Unless otherwise indicated, the term “optionally substituted” refers toa group in which none, one, or more than one of the hydrogen atoms hasbeen replaced with one or more group(s) individually and independentlyselected from: alkyl, heteroalkyl, haloalkyl, alkenyl, alkynyl,heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromaticring, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano,halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro,silyl, trihalomethanesulfonyl, oxo, and amino, including mono- anddi-substituted amino groups, and the protected derivatives of aminogroups. Such protective derivatives (and protecting groups that may formsuch protective derivatives) are known to those of skill in the art andmay be found in references such as Greene and Wuts, above. Inembodiments in which two or more hydrogen atoms have been substituted,the substituent groups may together form a ring.

Throughout the specification, groups and substituents thereof can bechosen by one skilled in the field to provide stable moieties andcompounds.

The term “carrier” refers to a compound that facilitates theincorporation of another compound into cells or tissues. For example,dimethyl sulfoxide (DMSO) is a commonly used carrier for improvingincorporation of certain organic compounds into cells or tissues.

The term “pharmaceutical agent” refers to a chemical compound orcomposition capable of inducing a desired therapeutic effect in apatient. In certain embodiments, a pharmaceutical agent comprises anactive agent, which is the agent that induces the desired therapeuticeffect. In certain embodiments, a pharmaceutical agent comprises aprodrug. In certain embodiments, a pharmaceutical agent comprisesinactive ingredients such as carriers, excipients, and the like.

The term “therapeutically effective amount” refers to an amount of apharmaceutical agent sufficient to achieve a desired therapeutic effect.

The term “prodrug” refers to a pharmaceutical agent that is convertedfrom a less active form into a corresponding more active form in vivo.

The term “pharmaceutically acceptable” refers to a formulation of acompound that does not significantly abrogate the biological activity, apharmacological activity and/or other properties of the compound whenthe formulated compound is administered to a patient. In certainembodiments, a pharmaceutically acceptable formulation does not causesignificant irritation to a patient.

The term “co-administer” refers to administering more than onepharmaceutical agent to a patient. In certain embodiments,co-administered pharmaceutical agents are administered together in asingle dosage unit. In certain embodiments, co-administeredpharmaceutical agents are administered separately. In certainembodiments, co-administered pharmaceutical agents are administered atthe same time. In certain embodiments, co-administered pharmaceuticalagents are administered at different times.

The term “patient” includes human and animal subjects.

The term “substantially pure” means an object species (e.g., compound)is the predominant species present (i.e., on a molar basis it is moreabundant than any other individual species in the composition). Incertain embodiments, a substantially purified fraction is a compositionwherein the object species comprises at least about 50 percent (on amolar basis) of all species present. In certain embodiments, asubstantially pure composition will comprise more than about 80%, 85%,90%, 95%, or 99% of all species present in the composition. In certainembodiments, the object species is purified to essential homogeneity(contaminant species cannot be detected in the composition byconventional detection methods) wherein the composition consistsessentially of a single species.

Certain Compounds

In certain embodiments, compounds of Formula (I) are provided:

-   -   or a salt, ester, amide, or prodrug thereof,    -   wherein    -   is a single or double bond;    -   W is selected from CH, CH—CH, O, S, NR⁶, and CO;    -   Y is N or CR⁹;    -   Z is N or C, and Z is N if W is CH and Y is CR⁹;    -   R⁴ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        an optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted non-aromatic ring, an        optionally substituted carbocycle, an optionally substituted        C₁-C₆ alkyl, an optionally substituted C₁-C₆ haloalkyl, an        optionally substituted C₁-C₆ heteroalkyl, an optionally        substituted C₁-C₆ alkenyl, an optionally substituted C₁-C₆        alkynyl, CO₂R⁶, SO₃R⁶, SO₂R⁶ and SO₂NR⁷R⁸;    -   R⁵ is selected from hydrogen, halogen, OR⁶, an optionally        substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆        haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an        optionally substituted C₁-C₆ haloheteroalkyl, an optionally        substituted C₁-C₆ alkenyl, and an optionally substituted C₁-C₆        alkynyl;    -   or R⁴ and R⁵ are linked to form an optionally substituted        non-aromatic ring;    -   each R⁶ is independently selected from an optionally substituted        aryl, an optionally substituted heteroaryl, and an optionally        substituted non-aromatic ring, each optionally fused with a        substituted aryl or a substituted heteroaryl, hydrogen, an        optionally substituted C₁-C₁₀ alkyl, an optionally substituted        C₁-C₁₀ haloalkyl, and an optionally substituted C₁-C₁₀        heteroalkyl;    -   each R⁷ and R⁸ is independently selected from an optionally        substituted aryl, an optionally substituted heteroaryl, an        optionally substituted non-aromatic ring, each optionally fused        with a substituted aryl or a substituted heteroaryl, hydrogen,        an optionally substituted C₁-C₁₀ alkyl, an optionally        substituted C₁-C₁₀ haloalkyl, an optionally substituted C₁-C₁₀        alkenyl, an optionally substituted C₁-C₁₀ alkynyl, and an        optionally substituted C₁-C₁₀ heteroalkyl, or R⁷ and R⁸ are        linked to form an optionally substituted non-aromatic ring;    -   R⁹ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        an optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted non-aromatic ring, an        optionally substituted C₁-C₆ alkyl, an optionally substituted        C₁-C₆ haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an        optionally substituted C₁-C₆ alkenyl, an optionally substituted        C₁-C₆ alkynyl, CO₂R⁶, SO₃R⁶, and SO₂NR⁷R⁸;    -   A is an optionally substituted aryl or an optionally substituted        heteroaryl group;    -   each optionally substituted group is either unsubstituted or        substituted with one or more groups independently selected from        alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl,        heterohaloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic ring,        hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano,        halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,        O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,        N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,        isothiocyanato, nitro, silyl, trihalomethanesulfonyl, ═O, ═S,        amino, and protected derivatives of amino groups.

In some embodiments, R⁴ is selected from hydrogen, halogen, OR⁶, CN,NR⁷R⁸, CH₂OR⁶, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted non-aromatic ring, an optionallysubstituted carbocycle, an optionally substituted C₁-C₆ alkyl, anoptionally substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆heteroalkyl, an optionally substituted C₁-C₆ alkenyl, an optionallysubstituted C₁-C₆ alkynyl, CO₂R⁶, SO₃R⁶, SO₂R⁶ and SO₂NR⁷R⁸.

In some embodiments, if R⁴ is pyrazolyl, the pyrazolyl is notsubstituted with aryl or heteroaryl groups.

In some embodiments, if R⁴ is oxazolyl, isoxazolyl, or imidazoyl, theoxazolyl, isoxazolyl, or imidazoyl radical is not substituted with arylor heteroaryl groups.

Some embodiments include a compound represented by Formula (I-A):

-   -   or a salt, ester, amide, or prodrug thereof,    -   wherein    -   X is N or CR⁵′, wherein R⁵′ is selected from hydrogen, halogen,        OR⁶, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        heteroalkyl, an optionally substituted C₁-C₆ haloheteroalkyl, an        optionally substituted C₁-C₆ alkenyl, and an optionally        substituted C₁-C₆ alkynyl;    -   R¹ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        CH₂NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        alkenyl, an optionally substituted C₁-C₆ alkynyl, an optionally        substituted C₁-C₆ heteroalkyl, CO₂R⁶, CONR⁷R⁸, SO₃R⁶, and        SO₂NR⁷R⁸;    -   R² and R³ are independently selected from hydrogen, halogen,        OR⁶, NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionally        substituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆        alkenyl, an optionally substituted C₁-C₆ alkynyl, and an        optionally substituted C₁-C₆ heteroalkyl.

Some embodiments include a compound represented by Formula (II), (III),or (IV):

-   -   or a salt, ester, amide, or prodrug thereof,    -   wherein:    -   W is selected from O, S, NR⁶, and CO;    -   X is N or CR⁵;    -   Y is N or CR⁹;    -   R⁴ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        an optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted non-aromatic ring, an        optionally substituted carbocycle, an optionally substituted        C₁-C₆ alkyl, an optionally substituted C₁-C₆ haloalkyl, an        optionally substituted C₁-C₆ heteroalkyl, an optionally        substituted C₁-C₆ alkenyl, an optionally substituted C₁-C₆        alkynyl, CO₂R⁶, SO₃R⁶, and SO₂NR⁷R⁸;    -   each R⁵ is independently selected from hydrogen, halogen, OR⁶,        an optionally substituted C₁-C₆ alkyl, an optionally substituted        C₁-C₆ haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an        optionally substituted C₁-C₆ haloheteroalkyl, an optionally        substituted C₁-C₆ alkenyl, and an optionally substituted C₁-C₆        alkynyl;    -   or R⁴ and R⁵ are linked to form an optionally substituted        non-aromatic ring;    -   each R⁶ is independently selected from hydrogen, an optionally        substituted aryl, an optionally substituted heteroaryl, an        optionally substituted non-aromatic ring, an optionally        substituted C₁-C₁₀ alkyl, an optionally substituted C₁-C₁₀        haloalkyl, and an optionally substituted C₁-C₁₀ heteroalkyl,        each optionally fused with a substituted aryl or a substituted        heteroaryl;    -   each R⁷ and R⁸ is independently selected from hydrogen, an        optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted non-aromatic ring, an        optionally substituted C₁-C₁₀ alkyl, an optionally substituted        C₁-C₁₀ haloalkyl, an optionally substituted C₁-C₁₀ alkenyl, an        optionally substituted C₁-C₁₀ alkynyl, and an optionally        substituted C₁-C₁₀ heteroalkyl, each optionally fused with a        substituted aryl or a substituted heteroaryl, or R⁷ and R⁸ are        linked to form an optionally substituted non-aromatic ring;    -   R⁹ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        an optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted non-aromatic ring, an        optionally substituted C₁-C₆ alkyl, an optionally substituted        C₁-C₆ haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an        optionally substituted C₁-C₆ alkenyl, an optionally substituted        C₁-C₆ alkynyl, CO₂R⁶, SO₃R⁶, and SO₂NR⁷R⁸;    -   A is an optionally substituted aryl or an optionally substituted        heteroaryl group;    -   each optionally substituted group is either unsubstituted or        substituted with one or more groups independently selected from        alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl,        heterohaloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic ring,        hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano,        halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,        O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,        N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,        isothiocyanato, nitro, silyl, trihalomethanesulfonyl, ═O, ═S,        amino, and protected derivatives of amino groups.

In some embodiments, if R⁴ is a pyrazolyl, oxazolyl, isoxazolyl, orimidazoyl radical in compounds of Formula (II), (III), or (IV), thepyrazolyl, oxazolyl, isoxazolyl, or imidazoyl radical is not substitutedwith aryl or heteroaryl groups.

In some specific embodiments, if R⁴ is a pyrazolyl radical in compoundsof Formula (II), (III), or (IV), the pyrazolyl is not substituted witharyl or heteroaryl groups.

Certain Synthetic Methods

In certain embodiments, compounds of the present invention can bysynthesized using the following Schemes.

Scheme I describes the synthesis of aminopyridine substitutedbenzothiazoles. An aminopyridine 1 is treated with a base such as NaHand reacted with 6-bromo-2-chlorobenzothiazole 2 to afford compounds ofstructure 3. Palladium catalyzed coupling of structure 3 with a boronicacid affords compounds of structure 4.

Scheme II describes the synthesis of aminopyridine substitutedbenzothiazoles. Aminopyridine 1 is converted to an isothiocyanate 5 andreacted with an aniline 6, to give a thiourea 7. The thiourea isoxidatively cyclized with, for example, bromine to give thebenzothiazole 4.

Scheme III describes the synthesis of aminopyridine substitutedimidazopyridines 10. A 2-halopyridine, such as compound 8, is coupledwith an aminoimidazopyridine, such as 9, under the influence of apalladium catalyst and a base to furnish products 10.

One of skill in the art will recognize that analogous synthetic schemesmay be used to synthesize similar compounds. One of skill will recognizethat compounds of the present invention may be synthesized using othersynthesis schemes. In certain embodiments, the invention provides a saltcorresponding to any of the compounds provided herein.

Certain Pharmaceutical Agents

Some embodiments include pharmaceutical agents. In some embodiments apharmaceutical agent can include a compound and/or composition providedherein and a pharmaceutical carrier. In certain embodiments, at leastone compound of Formula (I), (II), (III), or (IV), or a pharmaceuticallyacceptable salt, ester, amide, and/or prodrug thereof, either alone orcombined with one or more pharmaceutically acceptable carriers, forms apharmaceutical agent. Techniques for formulation and administration ofcompounds of the present embodiments may be found for example, in“Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa.,18th edition, 1990, which is incorporated herein by reference in itsentirety.

In certain embodiments, a pharmaceutical agent comprising one or morecompounds of the present embodiments is prepared using known techniques,including, but not limited to mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping ortabletting processes.

In certain embodiments, a pharmaceutical agent comprising one or morecompounds of the present embodiments is a liquid (e.g., a suspension,elixir and/or solution). In certain of such embodiments, a liquidpharmaceutical agent comprising one or more compounds of the presentembodiments is prepared using ingredients known in the art, including,but not limited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents.

In certain embodiments, a pharmaceutical agent comprising one or morecompounds of the present embodiments is a solid (e.g., a powder, tablet,and/or capsule). In certain of such embodiments, a solid pharmaceuticalagent comprising one or more compounds of the present embodiments isprepared using ingredients known in the art, including, but not limitedto, starches, sugars, diluents, granulating agents, lubricants, binders,and disintegrating agents.

In certain embodiments, a pharmaceutical agent comprising one or morecompounds of the present embodiments is formulated as a depotpreparation. Certain such depot preparations are typically longer actingthan non-depot preparations. In certain embodiments, such preparationsare administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. In certain embodiments,depot preparations are prepared using suitable polymeric or hydrophobicmaterials (for example an emulsion in an acceptable oil) or ion exchangeresins, or as sparingly soluble derivatives, for example, as a sparinglysoluble salt.

In certain embodiments, a pharmaceutical agent comprising one or morecompounds of the present embodiments comprises a delivery system.Examples of delivery systems include, but are not limited to, liposomesand emulsions. Certain delivery systems are useful for preparing certainpharmaceutical agents including those comprising hydrophobic compounds.In certain embodiments, certain organic solvents such asdimethylsulfoxide are used.

In certain embodiments, a pharmaceutical agent comprising one or morecompounds of the present embodiments comprises one or moretissue-specific delivery molecules designed to deliver thepharmaceutical agent to specific tissues or cell types. For example, incertain embodiments, pharmaceutical agents include liposomes coated witha tissue-specific antibody.

In certain embodiments, a pharmaceutical agent comprising one or morecompounds of the present embodiments comprises a co-solvent system.Certain of such co-solvent systems comprise, for example, benzylalcohol, a nonpolar surfactant, a water-miscible organic polymer, and anaqueous phase. In certain embodiments, such co-solvent systems are usedfor hydrophobic compounds. A non-limiting example of such a co-solventsystem is the VPD co-solvent system, which is a solution of absoluteethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolarsurfactant Polysorbate 80™, and 65% w/v polyethylene glycol 300. Theproportions of such co-solvent systems may be varied considerablywithout significantly altering their solubility and toxicitycharacteristics. Furthermore, the identity of co-solvent components maybe varied: for example, other surfactants may be used instead ofPolysorbate 80™; the fraction size of polyethylene glycol may be varied;other biocompatible polymers may replace polyethylene glycol, e.g.,polyvinyl pyrrolidone; and other sugars or polysaccharides maysubstitute for dextrose.

In certain embodiments, a pharmaceutical agent comprising one or morecompounds of the present embodiments comprises a sustained-releasesystem. A non-limiting example of such a sustained-release system is asemi-permeable matrix of solid hydrophobic polymers. In certainembodiments, sustained-release systems may, depending on their chemicalnature, release compounds over a period of hours, days, weeks or months.

Certain compounds used in pharmaceutical agent of the presentembodiments may be provided as pharmaceutically acceptable salts withpharmaceutically compatible counterions. Pharmaceutically compatiblesalts may be formed with many acids, including but not limited tohydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.

In certain embodiments, a pharmaceutical agent comprising one or morecompounds of the present embodiments comprises an active ingredient in atherapeutically effective amount. In certain embodiments, thetherapeutically effective amount is sufficient to prevent, alleviate orameliorate symptoms of a disease or to prolong the survival of thesubject being treated. Determination of a therapeutically effectiveamount is well within the capability of those skilled in the art.

In certain embodiments, a pharmaceutical agent comprising one or morecompounds of the present embodiments is formulated as a prodrug. Incertain embodiments, prodrugs are useful because they are easier toadminister than the corresponding active form. For example, in certaininstances, a prodrug may be more bioavailable (e.g., through oraladministration) than is the corresponding active form. In certaininstances, a prodrug may have improved solubility compared to thecorresponding active form. In certain embodiments, a prodrug is anester. In certain embodiments, such prodrugs are less water soluble thanthe corresponding active form. In certain instances, such prodrugspossess superior transmittal across cell membranes, where watersolubility is detrimental to mobility. In certain embodiments, the esterin such prodrugs is metabolically hydrolyzed to carboxylic acid. Incertain instances the carboxylic acid containing compound is thecorresponding active form. In certain embodiments, a prodrug comprises ashort peptide (polyaminoacid) bound to an acid group. In certain of suchembodiments, the peptide is metabolized to form the corresponding activeform.

In certain embodiments, a pharmaceutical agent comprising one or morecompounds of the present embodiments is useful for treating a conditionor disorder in a mammal, such as a human. Suitable administration routesinclude, but are not limited to, oral, rectal, transmucosal, intestinal,enteral, topical, suppository, through inhalation, intrathecal,intraventricular, intraperitoneal, intranasal, intraocular andparenteral (e.g., intravenous, intramuscular, intramedullary, andsubcutaneous). In certain embodiments, pharmaceutical intrathecals areadministered to achieve local rather than systemic exposures. Forexample, pharmaceutical agents may be injected directly in the area ofdesired effect (e.g., in the renal or cardiac area).

In certain embodiments, a pharmaceutical agent comprising one or morecompounds of the present embodiments is administered in the form of adosage unit (e.g., tablet, capsule, bolus, etc.). In certainembodiments, such dosage units comprise a compound or compositionprovided herein, such as a compound or composition comprising Formula(I), (II), (III), or (IV), in a dose from about 1 μg/kg of body weightto about 50 mg/kg of body weight, and from about 2 μg/kg of body weightto about 25 mg/kg of body weight, from about 10 μg/kg of body weight toabout 5 mg/kg of body weight. In certain embodiments, pharmaceuticalagents are administered as needed, once per day, twice per day, threetimes per day, or four or more times per day. It is recognized by thoseskilled in the art that the particular dose, frequency, and duration ofadministration depends on a number of factors, including, withoutlimitation, the biological activity desired, the condition of thepatient, and tolerance for the pharmaceutical agent.

In certain embodiments, a pharmaceutical agent comprising a compound ofthe present embodiments is prepared for oral administration. In certainof such embodiments, a pharmaceutical agent is formulated by combiningone or more compounds of the present embodiments with one or morepharmaceutically acceptable carriers. Certain of such carriers enablecompounds of the present embodiments to be formulated as tablets, pills,dragees, capsules, liquids, gels, syrups, slurries, suspensions and thelike, for oral ingestion by a patient. In certain embodiments,pharmaceutical agents for oral use are obtained by mixing one or morecompounds of the present embodiments and one or more solid excipient.Suitable excipients include, but are not limited to, fillers, such assugars, including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). In certain embodiments, such a mixture isoptionally ground and auxiliaries are optionally added. In certainembodiments, pharmaceutical agents are formed to obtain tablets ordragee cores. In certain embodiments, disintegrating agents (e.g.,cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof, such as sodium alginate) are added.

In certain embodiments, dragee cores are provided with coatings. Incertain of such embodiments, concentrated sugar solutions may be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquersolutions, and suitable organic solvents or solvent mixtures. Dyestuffsor pigments may be added to tablets or dragee coatings.

In certain embodiments, pharmaceutical agents for oral administrationare push-fit capsules made of gelatin. Certain of such push-fit capsulescomprise one or more compounds of the present embodiments in admixturewith one or more filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In certain embodiments, pharmaceutical agents for oraladministration are soft, sealed capsules made of gelatin and aplasticizer, such as glycerol or sorbitol. In certain soft capsules, oneor more compounds of the present embodiments are be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.

In certain embodiments, pharmaceutical agents are prepared for buccaladministration. Certain of such pharmaceutical agents are tablets orlozenges formulated in conventional manner.

In certain embodiments, a pharmaceutical agent is prepared foradministration by injection (e.g., intravenous, subcutaneous,intramuscular, etc.). In certain of such embodiments, a pharmaceuticalagent comprises a carrier and is formulated in aqueous solution, such aswater or physiologically compatible buffers such as Hanks's solution,Ringer's solution, or physiological saline buffer. In certainembodiments, other ingredients are included (e.g., ingredients that aidin solubility or serve as preservatives). In certain embodiments,injectable suspensions are prepared using appropriate liquid carriers,suspending agents and the like. Certain pharmaceutical agents forinjection are presented in unit dosage form, e.g., in ampoules or inmulti-dose containers. Certain pharmaceutical agents for injection aresuspensions, solutions or emulsions in oily or aqueous vehicles, and maycontain formulatory agents such as suspending, stabilizing and/ordispersing agents. Certain solvents suitable for use in pharmaceuticalagents for injection include, but are not limited to, lipophilicsolvents and fatty oils, such as sesame oil, synthetic fatty acidesters, such as ethyl oleate or triglycerides, and liposomes. Aqueousinjection suspensions may contain substances that increase the viscosityof the suspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, such suspensions may also contain suitablestabilizers or agents that increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.

In certain embodiments, a pharmaceutical agent is prepared fortransmucosal administration. In certain of such embodiments penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art.

In certain embodiments, a pharmaceutical agent is prepared foradministration by inhalation. Certain of such pharmaceutical agents forinhalation are prepared in the form of an aerosol spray in a pressurizedpack or a nebulizer. Certain of such pharmaceutical agents comprise apropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Incertain embodiments using a pressurized aerosol, the dosage unit may bedetermined with a valve that delivers a metered amount. In certainembodiments, capsules and cartridges for use in an inhaler orinsufflator may be formulated. Certain of such formulations comprise apowder mixture of a compound of the present embodiments and a suitablepowder base such as lactose or starch.

In certain embodiments, a pharmaceutical agent is prepared for rectaladministration, such as a suppositories or retention enema. Certain ofsuch pharmaceutical agents comprise known ingredients, such as cocoabutter and/or other glycerides.

In certain embodiments, a pharmaceutical agent is prepared for topicaladministration. Certain of such pharmaceutical agents comprise blandmoisturizing bases, such as ointments or creams. Exemplary suitableointment bases include, but are not limited to, petrolatum, petrolatumplus volatile silicones, lanolin and water in oil emulsions such asEucerin™, available from Beiersdorf (Cincinnati, Ohio). Exemplarysuitable cream bases include, but are not limited to, Nivea™ Cream,available from Beiersdorf (Cincinnati, Ohio), cold cream (USP), PurposeCream™, available from Johnson & Johnson (New Brunswick, N.J.),hydrophilic ointment (USP) and Lubriderm™, available from Pfizer (MorrisPlains, N.J.).

In certain embodiments, the formulation, route of administration anddosage for a pharmaceutical agent of the present embodiments can bechosen in view of a particular patient's condition. In certainembodiments, a pharmaceutical agent is administered as a single dose. Incertain embodiments, a pharmaceutical agent is administered as a seriesof two or more doses administered over one or more days.

In certain embodiments, a pharmaceutical agent of the presentembodiments is administered to a patient between about 0.1% and 500%, 5%and 200%, 10% and 100%, 15% and 85%, 25% and 75%, or 40% and 60% of anestablished human dosage. Where no human dosage is established, asuitable human dosage may be inferred from ED₅₀ or ID₅₀ values, or otherappropriate values derived from in vitro or in vivo studies.

In certain embodiments, a daily dosage regimen for a patient comprisesan oral dose of between 0.1 mg and 2000 mg, 5 mg and 1500 mg, 10 mg and1000 mg, 20 mg and 500 mg, 30 mg and 200 mg, or 40 mg and 100 mg of acompound of the present embodiments. In certain embodiments, a dailydosage regimen is administered as a single daily dose. In certainembodiments, a daily dosage regimen is administered as two, three, four,or more than four doses.

In certain embodiments, a pharmaceutical agent of the presentembodiments is administered by continuous intravenous infusion. Incertain of such embodiments, from 0.1 mg to 500 mg of a composition ofthe present embodiments is administered per day.

In certain embodiments, a pharmaceutical agent of the presentembodiments is administered for a period of continuous therapy. Forexample, a pharmaceutical agent of the present embodiments may beadministered over a period of days, weeks, months, or years.

Dosage amount, interval between doses, and duration of treatment may beadjusted to achieve a desired effect. In certain embodiments, dosageamount and interval between doses are adjusted to maintain a desiredconcentration of compound in a patient. For example, in certainembodiments, dosage amount and interval between doses are adjusted toprovide plasma concentration of a compound of the present embodiments atan amount sufficient to achieve a desired effect. In certain of suchembodiments the plasma concentration is maintained above the minimaleffective concentration (MEC). In certain embodiments, pharmaceuticalagents of the present embodiments are administered with a dosage regimendesigned to maintain a concentration above the MEC for 10-90% of thetime, between 30-90% of the time, or between 50-90% of the time.

In certain embodiments in which a pharmaceutical agent is administeredlocally, the dosage regimen is adjusted to achieve a desired localconcentration of a compound of the present embodiments.

In certain embodiments, a pharmaceutical agent may be presented in apack or dispenser device which may contain one or more unit dosage formscontaining the active ingredient. The pack may for example comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice may be accompanied by instructions for administration. The packor dispenser may also be accompanied with a notice associated with thecontainer in form prescribed by a governmental agency regulating themanufacture, use, or sale of pharmaceuticals, which notice is reflectiveof approval by the agency of the form of the drug for human orveterinary administration. Such notice, for example, may be the labelingapproved by the U.S. Food and Drug Administration for prescriptiondrugs, or the approved product insert. Compositions comprising acompound of the present embodiments formulated in a compatiblepharmaceutical carrier may also be prepared, placed in an appropriatecontainer, and labeled for treatment of an indicated condition.

In certain embodiments, a pharmaceutical agent is in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

Certain Therapeutic Methods

Some compounds and compositions provided herein, such as compoundsand/or compositions comprising Formula (I), (II), (III), and (IV) areuseful for the treatment of a variety of diseases and disorders.Examples of diseases and disorders include inflammatory disorders, cellproliferative disorders, and immune-related disorders, and disordersassociated with IRAK-mediated signal transduction.

Inflammation of tissues and organs occurs in a wide range of disordersand diseases and in certain variations results from activation of thecytokine family of receptors. Example inflammatory disorders associatedwith activation of IRAK kinases and/or disorders IRAK-mediated signaltransduction include skin disorders, respiratory disorders, and otherdisorders with an allergic component. These disorders are treated orprevented by modulation of IRAK activity, for example, by administrationof certain compounds and/or compositions provided herein. In someembodiments, methods of treating a subject in need thereof includeadministering an effective amount of a compound or composition providedherein. Some embodiments include treating a disorder responsive toinhibition of IRAK-mediated signal transduction.

Example skin disorders include dermatitis, cutaneous eosinophilias,Lichen planus, urticaria, psoriasis, pruritus, angioedemas, chronic skinulcers, conjunctivitis, vasculitides, or erythemas. Examples ofrespiratory disorders include asthma, rhinitis, chronic obstructivepulmonary disease, bronchitis, nasal polyposis, nasal congestion,farmer's lung, fibroid lung and cough. Other example diseases that maybe treated with the compounds and compositions provided herein includeosteoarthritis, rheumatoid arthritis, multiple sclerosis, cornealulcers, uveitis, pain and inflammatory bowel disease. More exampledisorders include diabetes, obesity, allergic disease, cancer, andsepsis.

In some embodiments, the compounds and compositions provided herein canbe administered in combination with an additional active agent. Examplesof other active agents include anti-inflammatory agents, analgesicagents, such as: opiate agonists; lipoxygenase inhibitors;cyclooxygenase inhibitors, such as cyclooxygenase-2 inhibitors;interleukin inhibitors, such as interleukin-1 receptor antagonist; NMDAantagonists; inhibitors of nitric oxide or inhibitors of the synthesisof nitric oxide; a non-steroidal anti-inflammatory agent; or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sulindac, tenidap, and the like. Insome embodiments, the instant compounds and/or compoistions may beadministered with: a potentiator such as caffeine, an H2-antagonist(e.g., ranitidine), simethicone, aluminum or magnesium hydroxide; adecongestant such as phenylephrine, phenylpropanolamine, pseudophedrine,oxymetazoline, ephinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxy-ephedrine; an antitussive such ascodeine, hydrocodone, caramiphen, carbetapentane, or dextromethorphan; adiuretic; and a sedating or non-sedating antihistamine.

More examples of additional active agents include (a) VLA-4 antagonists;(b) corticosteroids, such as beclomethasone, methylprednisolone,betamethasone, prednisone, prednisolone, dexamethasone, fluticasone andhydrocortisone, and corticosteroid analogs such as budesonide; (c)immunosuppressants such as cyclosporine (cyclosporine A, Sandimmune®,Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus,Rapamune®) and other FK-506 type immunosuppressants, and mycophenolate,e.g., mycophenolate mofetil (CellCept®); (d) antihistamines(H1-histamine antagonists) such as brompheniramine, chlorpheniramine,dexchlorpheniramine, triprolidine, clemastine, diphenhydramine,diphenylpyraline, tripelennamine, hydroxyzine, methdilazine,promethazine, trimeprazine, azatadine, cyproheptadine, antazoline,pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine,fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as β2-agonists (e.g., terbutaline, metaproterenol,fenoterol, isoetharine, albuterol, bitolterol and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (e.g., zafirlukast, montelukast, pranlukast,iralukast, pobilukast and SKB-106,203), leukotriene biosynthesisinhibitors (zileuton, BAY-1005); (f) non-steroidal antiinflammatoryagents (NSAIDs) such as propionic acid derivatives (e.g., alminoprofen,benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen,flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen,oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid andtioxaprofen), acetic acid derivatives (e.g., indomethacin, acemetacin,alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid,fentiazac, furofenac, ibufenac, isoxepac, oxepinac, sulindac, tiopinac,tolmetin, zidometacin and zomepirac), fenamic acid derivatives (e.g.,flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid andtolfenamic acid), biphenylcarboxylic acid derivative (e.g., diflunisaland flufenisal), oxicams (e.g., isoxicam, piroxicam, sudoxicam andtenoxicam), salicylates (e.g., acetyl salicylic acid, sulfasalazine andanalogs, mesalamine) and the pyrazolones (e.g., apazone, bezpiperylon,feprazone, mofebutazone, oxyphenbutazone and phenylbutazone); (g)cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®) androfecoxib (Vioxx®); (h) inhibitors of phosphodiesterase type IV(PDE-IV); (i) interleukin inhibitors, such as interleukin-I (IL-I)inhibitors, and chemokine receptor antagonists; j) cholesterol loweringagents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin,pravastatin, fluvastatin, atorvastatin and other statins), bile acidsequestrants (e.g., cholestyramine and colestipol), nicotinic acid(niacin), fibric acid derivatives (gemfibrozil, clofibrate, fenofibrateand benzafibrate), probucol and nitroglycerin; (k) anti-diabetic agentssuch as insulin, sulfonylureas (e.g., glyburide, meglinatide),biguanides, e.g., metformin (Glucophage®), α-glucosidase inhibitors(acarbose), thiazolidinone compounds, e.g., rosiglitazone (Avandia®),troglitazone (Rezulin®) and pioglitazone (Actos®); (l) preparations ofinterferon beta (interferon β-1α, interferon β-1β); (m) gold compoundssuch as auranofin and aurothioglucose, (n) etanercept (Enbrel®), (o)antibody therapies such as orthoclone (OKT3), daclizumab (Zenapax®),basiliximab (Simulect®), infliximab (Remicade®) and D2E6 TNF antibody,(p) lubricants or emollients such as petrolatum and lanolin, (q)keratolytic agents, (r) vitamin D3 derivatives, e.g., calcipotriene orcalcipotriol (Dovonex®), (s) PUVA, (t) anthralin (Drithocreme®), (u)etretinate (Tegison®) and isotretinoin, (v) multiple sclerosistherapeutic agents such as β-1β (Betaseron®), interferon β-1α (Avonex®),azathioprine (Imurek®, Imuran®), glatiramer acetate (Copaxone®), aglucocorticoid (e.g., prednisolone) and cyclophosphamide and (w) β3adrenergic receptor agonists, leptin or derivatives thereof, andneuropeptide Y (e.g., NPY5) antagonists; (x) other compounds such as5-aminosalicylic acid and prodrugs thereof; (y) DNA-alkylating agents(e.g., cyclophosphamide, ifosfamide), antimetabolites (e.g.,azathioprine, 6-mercaptopurine, methotrexate, a folate antagonist, and5-fluorouracil, a pyrimidine antagonist), microtubule disruptors (e.g.,vincristine, vinblastine, paclitaxel, colchicine, nocodazole andvinorelbine), DNA intercalators (e.g., doxorubicin, daunomycin andcisplatin), DNA synthesis inhibitors such as hydroxyurea, DNAcross-linking agents, e.g., mitomycin C, and hormone therapy (e.g.,tamoxifen, and flutamide).

In still other particular embodiments, compounds and compositionsprovided herein are administered for the treatment of rheumatoidarthritis, wherein the compounds are administered either alone or incombination with a second therapeutic agent selected from methotrexate,sulfasalazine, a COX-2 inhibitor, hydroxychloroquine, cyclosporine A,D-penicillamine, infliximab, etanercept, auranofin and aurothioglucose.

In yet other particular embodiments, the present compounds areadministered for the treatment of inflammatory bowel disease wherein thecompound of the invention is used alone or in combination with a secondtherapeutic agent selected from sulfasalazine and analogs (e.g.,olsalazine) mesalamine, corticosteroids (e.g., prednisone, prednisolone)and analogs (e.g., budesonide), azathioprine, 6-mercaptopurine,cyclosporine A, methotrextate, infliximab, or an IL-1 inhibitor.

In other particular embodiments, the present methods are directed to thetreatment of multiple sclerosis using a compound of the invention eitheralone or in combination with a second therapeutic agent selected frominterferon β-1β, interferon β-1α, azathioprine, glatiramer acetate, aglucocorticoid (e.g., prednisolone), and cyclophosphamide.

EXAMPLES

The following examples, including experiments and results achieved, areprovided for illustrative purposes only and are not to be construed aslimiting the present invention. Where chemical structures depict atomshaving an unfilled valency, it is to be understood that the valency issatisfied with one or more hydrogen atoms.

Example 1—Synthesis ofN-(4-(hydroxymethyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine(Compound 101, Structure 4 in Scheme I, R¹═CH₂OH, R⁴=4-pyridyl)

To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-amine(1.92 g, 8.0 mmol, 1 eq.) in anhydrous tetrahydrofuran (THF) (100 mL)was added NaH (2.25 g, 56.0 mmol, 7.0 eq) at 0° C., after stirring atroom temperature for 30 min, a solution of6-bromo-2-chlorobenzo[d]thiazole (2.0 g, 8.1 mmol, 1 eq) in THF (20 mL)was added dropwise. Then the reaction mixture was heated to 65° C. for 2hours. After cooling, water was added, the organic layer was separatedand the aqueous was extracted with EtOAc, dried and concentrated to give6-bromo-N-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)benzo[d]thiazol-2-amine(1.5 g, 37%) which was used directly without further purification. ¹HNMR (500 MHz, CDCl₃) δ 8.03 (d, J=9.0, 1H); 6.87 (d, J=2.6, 1H); 6.64(dd, J=9.0, 2.6, 1H); 4.58 (t, J=5.2, 1H); 3.67 (s, 3H); 3.21 (td,J=7.1, 5.2, 2H); 2.31 (t, J=7.5, 2H); 1.70-1.59 (m, 4H); 1.46-1.29 (m,10H).

To a 10 mL microwave tube was added6-bromo-N-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)benzo[d]thiazol-2-amine(400 mg, 1.03 mmol), pyridine-4-boronic acid (185 mg, 1.5 eq), K₂CO₃(425 mg, 3.09 mmol, 3 eq), Pd(dppf)Cl₂, (25 mg, 0.03 mmol, 0.03 eq),LiCl (130 mg, 3.09 mmol, 3 eq) and 3 mL of dioxane/H₂O (4:1). Themixture was stirred at 140° C. under microwave condition for 1 h. Aftercooling to room temperature (rt), the mixture was concentrated in vacuoand the residue was purified by flash chromatography to give 125 mg ofN-(4-(((tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine.

N-(4-(((Tert-butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine(1.8 g, 3.34 mmol, 1 eq.) was dissolved in 6 N HCl/MeOH (30 mL), and thesuspension was stirred at room temperature for 2 hours. After completionof the reaction, the solvent was evaporated and the residue was purifiedby chromatography to give 1.2 g ofN-(4-(hydroxymethyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine101. ¹HNMR (DMSO-d₆, 400 MHz) δ 8.95 (d, 2H), 8.75 (s, 1H), 8.45 (d,2H), 8.35 (d, 1H), 8.11 (d, 1H), 7.84 (d, 1H), 7.22 (s, 1H), 7.00 (d,1H), 4.60 (s, 2H). MS (ES-API): MH⁺=335.0. HPLC t_(R)=2.20 min.

Example 2—Synthesis of6-(pyridin-4-yl)-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine(Compound 102, Structure 4 in Scheme I, R¹═CH₂-pyrrolidin-1-yl,R⁴=4-pyridyl)

(2-((6-(Pyridin-4-yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)methanol101 (0.12 g, 0.36 mmol, 1 eq.) was dissolved in POCl3 (3 mL) under N2,and the suspension was stirred at 110° C. for 2 hours. After cooling,POCl3 was evaporated under reduced pressure and the residue was basifiedwith sat. Na2CO3 solution, then extracted with DCM, dried andconcentrated in vacuo to affordN-(4-(chloromethyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine(80 mg, 63%) which was used directly in the next step.

A solution ofN-(4-(chloromethyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine(80 mg, 0.23 mmol, 1 eq.) in 1 mL dioxane was treated with 15 mg ofpyrrolidine and 20 mg DIEA. The reaction mixture was stirred at 140° C.under microwave condition for 1 h. After cooling to rt, the mixture wasconcentrated in vacuo. The residue was washed with EtOH to afford6-(pyridin-4-yl)-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine102 without further purification (67 mg). ¹HNMR (CD₃OD, 400 MHz) δ 8.83(d, 2H), 8.60 (m, 1H), 8.54 (m, 1H), 8.46 (m, 2H), 8.10 (m, 1H), 7.92(d, 1H), 7.52 (s, 1H), 3.37 (d, 1H), 4.53 (s, 2H), 3.62 (br s, 2H), 3.25(m, 2H overlapping with signal from CD₃OD), 2.22 (m, 2H), 2.09 (m, 2H).MS (ES-API): MH⁺=388.1. HPLC t_(R)=2.16 min.

Examples 3-332

Compounds 103-439 were prepared in a similar fashion as described inExamples 1-2 and their structures, names, and found molecular mass ionnumbers are summarized in Table 1 (Example: E.g.; Compound: Cmpd).

TABLE 1 E.g. Structure Cmpd Name [M + H]⁺  3

103 6-(1H-pyrazol-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 377.1   4

104 N-(4-(piperazin-1- ylmethyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2- amine 403.1   5

105 1-(4-((2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)methyl)piperazin-1- yl)ethanone 445.1   6

106 1-(4-methylpiperazin-1-yl)-2-(2- ((6-(pyridin-4-yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)ethanone 445.1   7

107 6-(5-methyl-1H-pyrazol-4-yl)-N- (4-(pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine 391.1   8

108 5-(1H-pyrazol-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)thiazolo[5,4-b]pyridin-2- amine 378.1   9

109 N-(4-morpholinopyridin-2-yl)-6- (1H-pyrazol-4-yl)benzo[d]thiazol-2-amine 379.1   10

110 N-(4-morpholinopyridin-2-yl)-5- (1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-amine 380.1   11

111 (2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)methanol 324.0   12

112 N-(4-(4-(2- methoxyethyl)piperazin-1-yl)pyridin-2-yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine437.1   13

113 N-(4- ((dimethylamino)methyl)pyridin- 2-yl)-5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- amine 352.0   14

114 N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)-5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2- amine 448.1   15

115 N-(4-(isopropoxymethyl)pyridin- 2-yl)-6-(1H-pyrazol-4-yl)benzo[d]thiazol-2-amine 366.0   16

116 N-(4-((4-(2- methoxyethyl)piperazin-1- yl)methyl)pyridin-2-yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine 462.2   17

117 N-(4-((4-(2- methoxyethyl)piperazin-1-yl)methyl)pyridin-2-yl)-5-(1H- pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-amine 451.2   18

118 N-(4-(4-(2- methoxyethyl)piperazin-1-yl)pyridin-2-yl)-5-(5-methyl-1H- pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-amine 451.2   19

119 N-(4-((4-(2- methoxyethyl)piperazin-1- yl)methyl)pyridin-2-yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine 465.2   20

120 2-methoxy-1-(4-(2-((5-(pyridin- 4-yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4-yl)piperazin- 1-yl)ethanone 462.1   21

121 N-(4-(4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)-5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2- amine 468.1   22

122 2-methoxy-1-(4-((2-((5-(pyridin- 4-yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4- yl)methyl)piperazin-1- yl)ethanone 476.2   23

123 2-methoxy-1-(4-(2-((6-(pyridin- 4-yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)piperazin- 1-yl)ethanone 461.1   24

124 N-(4-((4- (methylsulfonyl)piperazin-1- yl)methyl)pyridin-2-yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine 482.1   25

125 (S)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine 419.1   26

126 (R)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine 419.1   27

127 N-(4-(isopropoxymethyl)pyridin- 2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine 377.2   28

128 N-(4-(isopropoxymethyl)- pyridin-2-yl)-5-(5-methyl-1H-pyrazol-4-yl)thiazolo[5,4- b]pyridin-2-amine 381.1   29

129 (S)-N-(4-((2-methylpyrrolidin-1- yl)methyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2- amine 402.1   30

130 N-(4-(isopropoxymethyl)pyridin- 2-yl)-5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2- amine 378.1   31

131 5-(1H-pyrazol-4-yl)-N-(4-(4- (3,3,3-trifluoropropyl)piperazin-1-yl)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine 475.2   32

132 N-(4-(4- (isopropylsulfonyl)piperazin-1-yl)pyridin-2-yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine485.1   33

133 N-(4-(4- (isopropylsulfonyl)piperazin-1-yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine 496.0  34

134 2-methoxy-1-(4-(2-((5- (pyrimidin-5-yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)ethanone 463.1   35

135 N-(4-(4- (methylsulfonyl)piperazin-1-yl)pyridin-2-yl)-5-(pyrimidin-5- yl)thiazolo[5,4-b]pyridin-2- amine469.1   36

136 2-((6-methyl-4-(pyrrolidin-3- ylamino)pyridin-2-yl)amino)benzo[d]thiazole-6- carbonitrile 351.1   37

137 N-(4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)-6-(4H- 1,2,4-triazol-4-yl)benzo[d]thiazol-2-amine 378.1   38

143 2-((4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)amino)benzo[d]thiazole-6- carbonitrile 394.95  39

144 5-(5-methyl-1H-pyrazol-4-yl)-N- (4-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine 409.1   40

146 N-(4-(4-(2- methoxyethyl)piperazin-1-yl)pyridin-2-yl)-5-(pyridazin-4- yl)thiazolo[5,4-b]pyridin-2- amine449.1   41 147 1-(4-(2-((5-ethylthiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)-2- methoxyethanone413.1   42

148 1-((2-((5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4- yl)methyl)pyrrolidin-2-one 403.1   43

149 1-((2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4- yl)methyl)pyrrolidin-2-one 392.1   44

150 2-methoxy-1-(4-(2-((5-(pyridin- 4-yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4-yl)piperidin- 1-yl)ethanone 461.1   45

151 N²-(benzo[d]thiazol-2-yl)-N⁴- (bicyclo[2.2.1]heptan-2-yl)-N⁶-((R)-pyrrolidin-3-yl)-1,3,5- triazine-2,4,6-triamine  46

152 N²-(bicyclo[2.2.1]heptan-2-yl)- N⁴-(6-methoxybenzo[d]thiazol-2-yl)-N⁶-(pyrrolidin-3-yl)-1,3,5- triazine-2,4,6-triamine  47

153 N²-(bicyclo[2.2.1]heptan-2-yl)- N⁴-(6-chlorobenzo[d]thiazol-2-yl)-N⁶-(pyrrolidin-3-yl)-1,3,5- triazine-2,4,6-triamine  48

154 2-((4-(bicyclo[2.2.1]heptan-2- ylamino)-6-(pyrrolidin-3-ylamino)-1,3,5-triazin-2- yl)amino)benzo[d]thiazole-6- carboxylic acid 49

155 N²-(benzo[d]thiazol-2-yl)-N⁴- ((1R,4S)-bicyclo[2.2.1]heptan-2-yl)-N⁶-((R)-pyrrolidin-3- yl)pyrimidine-2,4,6-triamine  50

156 2-((6-methoxybenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 370.1   51

157 2-((6-cyanobenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 365.0   52

158 2-((6-chlorobenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 374.0   53

159 (R)-2-((2-((4-(methylamino)-6- (pyrrolidin-3-ylamino)-1,3,5-triazin-2- yl)amino)benzo[d]thiazol-6- yl)oxy)ethanol  54

160 (S)-2-((6- methoxybenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 370.0   55

161 (S)-2-((6-cyanobenzo[d]thiazol- 2-yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 365.0   56 162 (R)-2-((6-cyanobenzo[d]thiazol-2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide 365.0   57

163 (S)-2-((6-chlorobenzo[d]thiazol- 2-yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 373.9   58

164 (R)-2-((6-chlorobenzo[d]thiazol- 2-yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 374.0   59

165 N-(2-aminoethyl)-2-((6- cyanobenzo[d]thiazol-2-yl)amino)isonicotinamide 339.0   60

166 N-(4-aminobutyl)-2-((6- cyanobenzo[d]thiazol-2-yl)amino)isonicotinamide 367.1   61

167 2-((6-cyanobenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-ylmethyl)isonicotinamide 379.1   62

168 2-((6-cyanobenzo[d]thiazol-2- yl)amino)-N-(piperidin-3-yl)isonicotinamide 379.1   63

169 2-((6-cyanobenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-2-ylmethyl)isonicotinamide 379.0   64

170 2-((4-(3-aminopiperidine-1- carbonyl)pyridin-2-yl)amino)benzo[d]thiazole-6- carbonitrile 379.0   65

171 N²-(6-methoxybenzo[d]thiazol-2- yl)-N⁴-(pyrrolidin-3-yl)pyridine-2,4-diamine 342.0   66

172 N²-(6-chlorobenzo[d]thiazol-2- yl)-N⁴-(pyrrolidin-3-yl)pyridine-2,4-diamine 346.0   67

173 (S)-2-((6-bromobenzo[d]thiazol- 2-yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 418.0   68

174 (S)-2-((6-cyanobenzo[d]thiazol- 2-yl)amino)-N-methyl-N-(pyrrolidin-3-yl)isonicotinamide 379.0   69

175 2-((4-(pyrrolidin-3- ylamino)pyridin-2- yl)amino)benzo[d]thiazole-6-carbonitrile 337.1   70

176 (S)-2-((6-(pyridin-4- yl)benzo[d]thiazol-2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide 417.1   71

177 (S)-2-((6-(pyridin-3- yl)benzo[d]thiazol-2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide 417.1   72

178 (S)-2-((6-(1-methyl-1H-pyrazol- 4-yl)benzo[d]thiazol-2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide 420.1   73

179 (S)-2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide 406.2   74

180 2-((7-methoxybenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 370.0   75

181 6-bromo-N-(4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 391.0   76

182 (S)-2-((6-cyanobenzo[d]thiazol- 2-yl)amino)-6-methyl-N-(pyrrolidin-3-yl)isonicotinamide 379.1   77

183 (S)-2-((7-cyanobenzo[d]thiazol- 2-yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 365.0   78

184 2-((4-(cyclopentylamino)pyridin- 2-yl)amino)benzo[d]thiazole-6-carbonitrile 336.0   79

185 1-(4-((2-((6- bromobenzo[d]thiazol-2- yl)amino)pyridin-4-yl)methyl)piperazin-1- yl)ethanone 445.9   80

186 1-(4-((2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4- yl)methyl)piperazin-1- yl)ethanone  81

187 N-(4-(piperidin-1- ylmethyl)pyridin-2-yl)-6-(1H-pyrazol-4-yl)benzo[d]thiazol-2- amine  82

188 2-((5-methyl-4-(pyrrolidin-3- ylamino)pyridin-2-yl)amino)benzo[d]thiazole-6- carbonitrile 351.1   83

189 6-(pyridin-3-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine  84

190 1-((2-((6-bromobenzo[d]thiazol- 2-yl)amino)pyridin-4-yl)methyl)piperidin-4-ol  85

191 2-(((2-((6-bromobenzo[d]thiazol- 2-yl)amino)pyridin-4-yl)methyl)(methyl)amino)ethanol  86

192 6-bromo-N-(4- ((dimethylamino)methyl)pyridin-2-yl)benzo[d]thiazol-2-amine  87

193 6-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-yl)amino)-N-(pyrrolidin-3-yl)picolinamide 406.1   88

194 6-(1H-pyrazol-5-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine  89

195 2-((4-((2- aminopropyl)amino)pyridin-2- yl)amino)benzo[d]thiazole-6-carbonitrile 325.1   90

196 2-((4-((1-aminopropan-2- yl)amino)pyridin-2-yl)amino)benzo[d]thiazole-6- carbonitrile 325.1   91

197 N-((2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)methyl)methanesulfonamide 412.1   92

198 N-(4-(piperidin-1- ylmethyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2- amine 402.1   93

199 N-(4- ((dimethylamino)methyl)pyridin- 2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine 362.1   94

200 4-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-yl)amino)-N-(pyrrolidin-3-yl)picolinamide 406.1   95

201 6-(6-methoxypyridin-3-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 418.2   96

202 N-(4-(4-methylpiperazin-1- yl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine 403.1   97

203 6-(pyrimidin-5-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 389.1   98

204 N-(4-((4-methylpiperazin-1- yl)methyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2- amine 417.1   99

205 6-(2-methylpyridin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 402.1  100

206 2-(2-((6-(pyridin-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)acetic acid 363.0  101

207 1,1-dimethyl-3-((2-((6-(pyridin- 4-yl)benzo[d]thiazol-2-yl)amino)pyridin-4- yl)methyl)urea 405.1  102

208 6-(3-methoxypyridin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 418.1  103

209 6-(2-methoxypyridin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 418.1  104

210 6-(2-chloropyridin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 422.0  105

211 6-(3-methylpyridin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 402.1  106

212 2-(2-((6-(pyridin-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)-N-(2- (pyrrolidin-1-yl)ethyl)acetamide 459.1  107

213 N-(4- ((methylamino)methyl)pyridin-2- yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine 348.1  108

214 3-(2-((4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)amino)benzo[d]thiazol-6- yl)benzonitrile 412.1  109

215 N-(4-morpholinopyridin-2-yl)-6- (pyridin-4-yl)benzo[d]thiazol-2-amine 390.1  110

216 N-(4-((3-methoxypyrrolidin-1- yl)methyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2- amine 418.1  111

217 N-(4-((4- (methylsulfonyl)piperazin-1- yl)methyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2- amine 481.0  112

218 6-(2-methoxypyrimidin-5-yl)-N- (4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 419.1  113

219 3-(piperidin-1-yl)-N-((2-((6- (pyridin-4-yl)benzo[d]thiazol-2-yl)amino)pyridin-4- yl)methyl)propanamide 473.2  114

220 6-(benzo[c][1,2,5]oxadiazol-5- yl)-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2- yl)benzo[d]thiazol-2-amine 429.1  115

221 1-methyl-4-(2((6-(pyridin-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)piperazin- 2-one 417.1  116

222 2-(4-(2-((6-(pyridin-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)piperazin- 1-yl)ethanol 433.1  117

223 N-methyl-4-((2-((6-(pyridin-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4- yl)methyl)piperazine-1- carboxamide 460.2  118

224 Methyl 2-(2-((6-(pyridin-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)acetate 377.1  119

225 2-(methyl(2-((6-(pyridin-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4- yl)amino)ethanol 378.1  120

226 1-((2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)methyl)pyrrolidin-3-ol 404.1  121

227 N-(4-((4-methylpiperazin-1- yl)methyl)pyridin-2-yl)-6-(pyrimidin-5-yl)benzo[d]thiazol- 2-amine 418.2  123

228 2-((2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)amino)ethanol 364.1  124

229 7-methyl-6-(pyridin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 402.1  125

230 5-methyl-6-(pyridin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 402.1  126

231 N-(pyridin-2-yl)-6-(pyridin-4- yl)benzo[d]thiazol-2-amine 305.0  127

232 6-(2-aminopyrimidin-5-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 404.1  128

233 2-(2-((6-(pyridin-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)-1-(pyrrolidin-1-yl)ethanone 416.1  129

234 N-(4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)-6-(2-(trifluoromethyl)pyridin-4- yl)benzo[d]thiazol-2-amine 456.1  130

235 1-methyl-N-((2-((6-(pyridin-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4- yl)methyl)pyrrolidine-2- carboxamide 445.1  131

236 5-(pyridin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)thiazolo[5,4-b]pyridin-2- amine 389.1  132

237 5-(pyrimidin-5-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)thiazolo[5,4-b]pyridin-2- amine 390.1  133

238 N-(4-(aminomethyl)pyridin-2- yl)-6-(pyrimidin-5-yl)benzo[d]thiazol-2-amine 335.1  134

239 N-methyl-2-(2-((6-(pyridin-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)acetamide 376.1  135

240 N-(2-hydroxyethyl)-2-(2-((6- (pyridin-4-yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)acetamide 406.0  136

242 N-(4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)-6-(1H- 1,2,4-triazol-1-yl)benzo[d]thiazol-2-amine 378.1  137

243 1-(3-hydroxypyrrolidin-1-yl)-2- (2-((6-(pyridin-4-yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)ethanone 432.0  138

244 N-((2-((6-(pyrimidin-5- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)methyl)methanesulfonamide 413.0  139

245 N-(4-morpholinopyridin-2-yl)-6- (4H-1,2,4-triazol-4-yl)benzo[d]thiazol-2-amine 380.1  140

246 N-(4-(4-methylpiperazin-1- yl)pyridin-2-yl)-6-(4H-1,2,4-triazol-4-yl)benzo[d]thiazol-2- amine 393.2  141

247 N-(4-(piperazin-1-yl)pyridin-2- yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine 389.1  142

248 N-(4-(4-methylpiperazin-1- yl)pyridin-2-yl)-5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- amine 393.0  143

249 N-(4-(piperazin-1-yl)pyridin-2- yl)-5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- amine 379.1  144

250 6-(1H-imidazol-1-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 377.2  145

251 6-(5-methyl-1H-pyrazol-4-yl)-N- (4-morpholinopyridin-2-yl)benzo[d]thiazol-2-amine 393.1  146

252 6-(5-methyl-1H-pyrazol-4-yl)-N- (4-(4-methylpiperazin-1-yl)pyridin-2-yl)benzo[d]thiazol- 2-amine 406.1  147

253 N-(4-(piperazin-1-yl)pyridin-2- yl)-5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-amine 390.1  148

254 N-(4-(pyrrolidin-3- ylamino)pyridin-2-yl)-6-cyanobenzo[d]thiazol-2-amine 149

255 N-(4-(4-methylpiperazin-1- yl)pyridin-2-yl)-6-(1H-pyrazol-4-yl)benzo[d]thiazol-2-amine 392.1  150

256 N-(4-morpholinopyridin-2-yl)-5- (pyridin-4-yl)thiazolo[5,4-b]pyridin-2-amine 391.0  151

257 N-(4-(4-methylpiperazin-1- yl)pyridin-2-yl)-5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2- amine 404.0  152

258 N-(4-(piperazin-1-yl)pyridin-2- yl)-6-(1H-pyrazol-4-yl)benzo[d]thiazol-2-amine 378.0  153

259 6-(pyridazin-4-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 389.0  154

260 N-(4- ((methylamino)methyl)pyridin-2- yl)-6-(1H-pyrazol-4-yl)benzo[d]thiazol-2-amine 337.0  155

261 N-(4- ((dimethylamino)methyl)pyridin- 2-yl)-6-(1H-pyrazol-4-yl)benzo[d]thiazol-2-amine 351.1  156

262 N-(pyrazin-2-yl)-6-(pyridin-4- yl)benzo[d]thiazol-2-amine 306.0  157

263 N-(4-(azetidin-1- ylmethyl)pyridin-2-yl)-6-(1H-pyrazol-4-yl)benzo[d]thiazol-2- amine 363.0  158

264 N-(4-(4-methyl-1,4-diazepan-1- yl)pyridin-2-yl)-5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- amine 407.1  159

265 N-(4-(4-benzylpiperazin-1- yl)pyridin-2-yl)-5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- amine 469.1  160

266 5-(2-((4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)amino)thiazolo[5,4-b]pyridin- 5-yl)pyrimidine-2-carbonitrile 415.0 161

267 1-(4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4-yl)piperazin- 1-yl)-2-(dimethylamino)ethanone 464.0 162

268 2-hydroxy-N-((2-((6-(pyridin-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4- yl)methyl)acetamide 392.0  163

269 2-(4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4-yl)piperazin- 1-yl)ethanol 423.1  164

270 1-(4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4-yl)piperazin- 1-yl)-2-methoxyethanone 451.1  165

271 5-(2-((4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)amino)benzo[d]thiazol-6- yl)pyrimidine-2-carbonitrile 414.0  166

272 (2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4-yl)methanol 325.0  167

273 N²-(6-(pyridin-4- yl)benzo[d]thiazol-2-yl)pyridine- 2,6-diamine320.0  168

274 6-(1H-pyrrol-3-yl)-N-(4- (pyrrolidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 376.1  169

275 1-(4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4-yl)piperazin- 1-yl)-2-hydroxyethanone 437.1  170

276 N-(4- ((methylamino)methyl)pyridin-2- yl)-5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- amine 338.0  171

277 N-(4-(aminomethyl)pyridin-2- yl)-5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- amine 324.0  172

278 1-(2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)ethanol 338.0  173

279 N-(4-(4- (methylsulfonyl)piperazin-1-yl)pyridin-2-yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine457.1  174

280 2-(2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)propan-2- ol 352.0  175

281 N-(4-(methoxymethyl)pyridin-2- yl)-6-(1H-pyrazol-4-yl)benzo[d]thiazol-2-amine 338.0  176

282 1-(4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4-yl)piperazin- 1-yl)-3-(dimethylamino)propan- 1-one478.2  177

283 (2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)-3-fluoropyridin-4- yl)methanol 343.0  178

284 1-(4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4-yl)piperazin- 1-yl)-3-(pyrrolidin-1-yl)propan- 1-one504.2  179

285 N-(4- ((dimethylamino)methyl)pyridin-2-yl)-6-(5-methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine 365.1  180

286 6-(5-methyl-1H-pyrazol-4-yl)-N- (4- ((methylamino)methyl)pyridin-2-yl)benzo[d]thiazol-2-amine 351.1  181

287 N-(4-(aminomethyl)pyridin-2- yl)-6-(5-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-amine 337.0  182

288 6-(5-methyl-1H-pyrazol-4-yl)-N- (4-(piperidin-1-ylmethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 405.1  183

289 6-(5-methyl-1H-pyrazol-4-yl)-N- (4-(morpholinomethyl)pyridin-2-yl)benzo[d]thiazol-2-amine 407.2  184

290 N-(4- ((dimethylamino)methyl)pyridin-2-yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine366.1  185

291 5-(5-methyl-1H-pyrazol-4-yl)-N- (4-(piperidin-1-ylmethyl)pyridin-2-yl)thiazolo[5,4-b]pyridin-2- amine 406.1  186

292 5-(5-methyl-1H-pyrazol-4-yl)-N- (4-((2-methylpyrrolidin-1-yl)methyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine 406.1  187

293 N-(4-(isoindolin-2- ylmethyl)pyridin-2-yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine 440.1  188

294 N-(4-((3-methoxypyrrolidin-1- yl)methyl)pyridin-2-yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine 422.2  189

295 5-(5-methyl-1H-pyrazol-4-yl)-N- (4-(morpholinomethyl)pyridin-2-yl)thiazolo[5,4-b]pyridin-2- amine 408.1  190

296 N-(4-(aminomethyl)pyridin-2- yl)-6-(1H-pyrazol-4-yl)benzo[d]thiazol-2-amine 323.1  191

297 5-(5-methyl-1H-pyrazol-4-yl)-N- (4- ((methylamino)methyl)pyridin-2-yl)thiazolo[5,4-b]pyridin-2- amine 352.1  192

298 N-(4-(azepan-1- ylmethyl)pyridin-2-yl)-5-(5- methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- amine 420.1  193

299 N-(4-(((1S,4R)- bicyclo[2.2.1]heptan-2-ylamino)methyl)pyridin-2-yl)-5- (5-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- amine 432.2  194

300 5-(5-methyl-1H-pyrazol-4-yl)-N- (4-((3-phenylpyrrolidin-1-yl)methyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine 468.1  195

301 N-(4-(azepan-1- ylmethyl)pyridin-2-yl)-6-(5- methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-amine 419.2  196

302 6-(5-methyl-1H-pyrazol-4-yl)-N- (4-((2-methylpyrrolidin-1-yl)methyl)pyridin-2- yl)benzo[d]thiazol-2-amine 405.2  197

303 N-(4-(isoindolin-2- ylmethyl)pyridin-2-yl)-6-(5-methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine 439.1  198

304 N-(4-((3-methoxypyrrolidin-1- yl)methyl)pyridin-2-yl)-6-(5-methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine 421.2  199

305 1-((2-((6-(5-methyl-1H-pyrazol- 4-yl)benzo[d]thiazol-2-yl)amino)pyridin-4- yl)methyl)pyrrolidin-3-ol 407.1  200

306 N-(4-(azetidin-1- ylmethyl)pyridin-2-yl)-5-(5- methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- amine 378.1  201

307 1-((2-((5-(5-methyl-1H-pyrazol- 4-yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4- yl)methyl)pyrrolidin-3-ol 408.1  202

308 N-(4-(azetidin-1- ylmethyl)pyridin-2-yl)-6-(5- methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-amine 377.1  203

309 6-(5-methyl-1H-pyrazol-4-yl)-N- (4-((3-phenylpyrrolidin-1-yl)methyl)pyridin-2- yl)benzo[d]thiazol-2-amine 467.1  204

310 N-(4-((4-(2- methoxyethyl)piperazin-1- yl)methyl)pyridin-2-yl)-6-(5-methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine 464.1  205

311 N-(4-((4-(2- methoxyethyl)piperazin-1- yl)methyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2- amine 461.2  206

312 N-(4-((4-(2- methoxyethyl)piperazin-1-yl)methyl)pyridin-2-yl)-6-(1H- pyrazol-4-yl)benzo[d]thiazol-2- amine450.2  207

313 6-(5-methyl-1H-pyrazol-4-yl)-N- (4-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2- yl)benzo[d]thiazol-2-amine 484.0  208

314 N-(4-(aminomethyl)pyridin-2- yl)-5-(5-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- amine 338.1  209

315 N-(4-((lS,4R)-2- azabicyclo[2.2.1]heptan-2-ylmethyl)pyridin-2-yl)-5-(5- methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- amine 418.1  210

316 N-(4-(4-(2- methoxyethyl)piperazin-1-yl)pyridin-2-yl)-6-(5-methyl-1H- pyrazol-4-yl)benzo[d]thiazol-2- amine450.1  211

317 2-methoxy-1-(4-(2-((6-(5- methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin-1-yl)ethanone 465.0  212

318 N-(4-((1S,4R)-2- azabicyclo[2.2.1]heptan-2-ylmethyl)pyridin-2-yl)-6-(5- methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-amine 213

319 N-(4-(((1S,4R)- bicyclo[2.2.1]heptan-2-ylamino)methyl)pyridin-2-yl)-6- (5-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-amine 214

320 N-(4-(4-(2- methoxyethyl)piperazin-1-yl)pyridin-2-yl)-6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-amine 436.1  215

321 N-(4-((3,3-dimethylpyrrolidin-1- yl)methyl)pyridin-2-yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine 420.2  216

322 N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine 447.1  217

323 5-(5-methyl-1H-pyrazol-4-yl)-N- (4-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine 471.1  218

324 N-(4-((3,3-dimethylpyrrolidin-1- yl)methyl)pyridin-2-yl)-6-(5-methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine 419.2  219

325 2-methoxy-1-(4-((2-((6-(5- methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2- yl)amino)pyridin-4- yl)methyl)piperazin-1-yl)ethanone 478.2  220

326 6-(1H-pyrazol-4-yl)-N-(4- ((pyridin-3- yloxy)methyl)pyridin-2-yl)benzo[d]thiazol-2-amine 401.0  221

327 N-(4-(4- (methylsulfonyl)piperazin-1- yl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2-amine 467.1  222

328 N-(4-(4- (methylsulfonyl)piperazin-1-yl)pyridin-2-yl)-6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-amine 456.1  223

329 N-(4-((4- (methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)-6-(1H- pyrazol-4-yl)benzo[d]thiazol-2- amine470.1  224

330 N-(4-((4- (methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-yl)-5-(1H- pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-amine 471.1  225

331 2-methoxy-1-(4-(2-((6-(5- methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)piperazin- 1-yl)ethanone 464.2  226

332 2-methoxy-1-(4-((2-((6-(pyridin- 4-yl)benzo[d]thiazol-2-yl)amino)pyridin-4- yl)methyl)piperazin-1- yl)ethanone 475.2  227

334 1-(4-((2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4- yl)methyl)piperazin-1-yl)-2- methoxyethanone 464.2 228

335 2-methoxy-1-(4-((2-((5-(5- methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4- yl)methyl)piperazin-1-yl)ethanone 479.2  229

336 1-(4-((2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4- yl)methyl)piperazin-1-yl)-2- methoxyethanone 465.2 230

337 6-(5-methyl-1H-pyrazol-4-yl)-N- (4-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2- yl)benzo[d]thiazol-2-amine 470.1  231

338 1-(4-(2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-yl)amino)pyridin-4-yl)piperazin- 1-yl)-2-methoxyethanone 450.1  232

339 4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4-yl)-1- methylpiperazin-2-one 407.1  233

340 5-(5-methyl-1H-pyrazol-4-yl)-N- (4-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine 485.1  234

341 6-(5-methyl-1H-pyrazol-4-yl)-N- (4-(piperazin-1-yl)pyridin-2-yl)benzo[d]thiazol-2-amine 235

342 1-((2-((6-(1H-pyrazol-4- yl)benzo[d]thiazol-2- yl)amino)pyridin-4-yl)methyl)pyrrolidin-3-ol 393.1  236

343 (R)-6-(5-methyl-1H-pyrazol-4- yl)-N-(4-((2-methylpyrrolidin-1-yl)methyl)pyridin-2- yl)benzo[d]thiazol-2-amine 405.1  237

344 (R)-5-(5-methyl-1H-pyrazol-4- yl)-N-(4-((2-methylpyrrolidin-1-yl)methyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine 406.1  238

345 (S)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-6-(5-methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine 421.1  239

346 (R)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-6-(5-methyl-1H-pyrazol-4- yl)benzo[d]thiazol-2-amine 421.1  240

347 (S)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine 422.1  241

348 (R)-N-(4-((2-methylpyrrolidin-1- yl)methyl)pyridin-2-yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine 403.2  242

349 N-(4-(isopropoxymethyl)pyridin- 2-yl)-5-(1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- amine 367.0  243

350 (S)-6-(5-methyl-1H-pyrazol-4- yl)-N-(4-((2-methylpyrrolidin-1-yl)methyl)pyridin-2- yl)benzo[d]thiazol-2-amine 405.1  244

351 (R)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine 422.1  245

352 (R)-N-(4-((2-methylpyrrolidin-1- yl)methyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2- amine 402.1  246

353 (S)-N-(4-((2-methylpyrrolidin-1- yl)methyl)pyridin-2-yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine 403.1  247

354 (S)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2- amine 418.1  248

355 (R)-N-(4-((3-methoxypyrrolidin- 1-yl)methyl)pyridin-2-yl)-6-(pyridin-4-yl)benzo[d]thiazol-2- amine 418.1  249

356 N-(4- ((cyclopentyloxy)methyl)pyridin- 2-yl)-6-(1H-pyrazol-4-yl)benzo[d]thiazol-2-amine 392.1  250

357 6-(1H-pyrazol-4-yl)-N-(4- (((tetrahydro-2H-pyran-4-yl)oxy)methyl)pyridin-2- yl)benzo[d]thiazol-2-amine 408.1  251

358 (S)-5-(5-methyl-1H-pyrazol-4- yl)-N-(4-((2-methylpyrrolidin-1-yl)methyl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine 406.1  252

359 N-(4-(isopropoxymethyl)pyridin- 2-yl)-6-(5-methyl-1H-pyrazol-4-yl)benzo[d]thiazol-2-amine 380.1  253

360 N-(4-(4-(2- isopropoxyethyl)piperazin-1-yl)pyridin-2-yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine465.2  254

361 5-(pyridin-4-yl)-N-(4-(4-(3,3,3- trifluoropropyl)piperazin-1-yl)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine 486.2  255

362 N-(4-(4-(2- isopropoxyethyl)piperazin-1-yl)pyridin-2-yl)-5-(5-methyl-1H- pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-amine 479.2  256

363 5-(5-methyl-1H-pyrazol-4-yl)-N- (4-(4-(3,3,3-trifluoropropyl)piperazin-1- yl)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine 489.0  257

364 N-(4-(4-(2- isopropoxyethyl)piperazin-1-yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine 476.2 258

365 N-(4-(4-(1-methoxpropan-2- yl)piperazin-1-yl)pyridin-2-yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine 465.1  259

366 6-(5-methyl-1H-pyrazol-4-yl)-N- (4-(4-(3,3,3-trifluoropropyl)piperazin-1- yl)pyridin-2-yl)benzo[d]thiazol- 2-amine488.1  260

367 (S)-N-(4-(3-methyl-4- (methylsulfonyl)piperazin-1-yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine 482.1 261

368 N-(4-(4-(2- isopropoxyethyl)piperazin-1-yl)pyridin-2-yl)-6-(1H-pyrazol-4- yl)benzo[d]thiazol-2-amine 464.1  262

369 N-(4-(4- (isopropylsulfonyl)piperazin-1-yl)pyridin-2-yl)-5-(5-methyl-1H- pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-amine 499.2  263

370 2,2-dimethyl-1-(4-(2-((5-(5- methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin-1-yl)propan-1-one 477.1  264

371 N-(4-(4-(2- isopropoxyethyl)piperazin-1-yl)pyridin-2-yl)-6-(pyridin-4- yl)benzo[d]thiazol-2-amine 475.2  265

372 6-(pyridin-4-yl)-N-(4-(4-(3,3,3- trifluoropropyl)piperazin-1-yl)pyridin-2-yl)benzo[d]thiazol- 2-amine 485.1  266

373 (S)-2-methoxy-1-(2-methyl-4-(2- ((5-(5-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin-1-yl)ethanone 479.2  267

374 (S)-2-methoxy-1-(2-methyl-4-(2- ((5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)ethanone 476.1  268

375 (S)-5-(5-methyl-1H-pyrazol-4- yl)-N-(4-(3-methyl-4-(methylsulfonyl)piperazin-1- yl)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine 485   269

376 (R)-N-(4-(4-(2-methoxyethyl)-3- methylpiperazin-1-yl)pyridin-2-yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine 465.1 270

377 6-(1H-pyrazol-4-yl)-N-(4-(4- (3,3,3-trifluoropropyl)piperazin-1-yl)pyridin-2- yl)benzo[d]thiazol-2-amine 474.1  271

378 N-(4-(4-(2- isopropoxyethyl)piperazin-1-yl)pyridin-2-yl)-6-(5-methyl-1H- pyrazol-4-yl)benzo[d]thiazol-2- amine478.2  272

379 (R)-2-methoxy-1-(3-methyl-4-(2- ((5-(5-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin-1-yl)ethanone 479.2  273

380 (R)-N-(4-(2-methyl-4- (methylsulfonyl)piperazin-1-yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine 482.1 274

381 (S)-N-(4-(4-(2-methoxyethyl)-3- methylpiperazin-1-yl)pyridin-2-yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine 465.2 275

382 (S)-N-(4-(4-(2-methoxyethyl)-3- methylpiperazin-1-yl)pyridin-2-yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine 462.1  276

383 (R)-N-(4-(4-(2-methoxyethyl)-3- methylpiperazin-1-yl)pyridin-2-yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine 462.1  277

384 1-(4-(2-((5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4-yl)piperazin- 1-yl)-2-isopropoxyethanone 479.1  278

385 2-isopropoxy-1-(4-(2-((5-(5- methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin-1-yl)ethanone 493.1  279

386 2-isopropoxy-1-(4-(2-((5- (pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)ethanone 490.1  280

387 (R)-2-methoxy-1-(3-methyl-4-(2- ((5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)ethanone 476.1  281

388 (R)-5-(5-methyl-1H-pyrazol-4- yl)-N-(4-(2-methyl-4-(methylsulfonyl)piperazin-1- yl)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine 485.1  282

389 (R)-2-methoxy-1-(2-methyl-4-(2- ((5-(5-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- yl)amino)pyridin-4-yl)piperazin-1-yl)ethanone 479.2  283

390 (R)-2-methoxy-1-(2-methyl-4-(2- ((5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)ethanone 476.1  284

391 2-methoxy-1-(4-(2-((5-(2- methylpyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)ethanone 476.1  285

392 (R)-N-(4-(3-methyl-4- (methylsulfonyl)piperazin-1-yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine 482.0 286

393 (S)-5-(5-methyl-1H-pyrazol-4- yl)-N-(4-(3-methyl-4-(methylsulfonyl)piperazin-1- yl)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine 485.1  287

394 N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)-5-(2-methylpyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine 462.1  288

395 5-(2-methylpyridin-4-yl)-N-(4- (4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine 482.0  289

396 2-methoxy-1-(4-(2-((5- (pyridazin-4-yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4- yl)piperazin-1-yl)ethanone 463.0  290

397 N-(4-(4- (methylsulfonyl)piperazin-1-yl)pyridin-2-yl)-5-(pyridazin-4- yl)thiazolo[5,4-b]pyridin-2- amine469.1  291

398 (S)-N-(4-(4-(2-methoxyethyl)-2- methylpiperazin-1-yl)pyridin-2-yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine 462.1  292

399 (S)-N-(4-(4-(2-methoxyethyl)-2- methylpiperazin-1-yl)pyridin-2-yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine 465.1 293

400 (R)-N-(4-(4-(2-methoxyethyl)-2- methylpiperazin-1-yl)pyridin-2-yl)-5-(pyridin-4-yl)thiazolo[5,4- b]pyridin-2-amine 462.1  294

401 N-(4-(4-(2- methoxyethyl)piperidin-1- yl)pyridin-2-yl)-5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2- amine 447.1  295

402 N-(4-(4-(2- methoxyethyl)piperidin-1-yl)pyridin-2-yl)-5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine436.1  296

403 N⁴-(2-methoxyethyl)-N⁴-methyl- N²-(5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-yl)pyridine-2,4- diamine 393.1  297

404 N-(4-((1S,4S)-5-(2- methoxyethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)-5-(5-methyl-1H- pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-amine 463.1  298

405 5-(5-methyl-1H-pyrazol-4-yl)-N- (4-(4-(pyridin-2-yl)piperazin-1-yl)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine 470.2  299

406 N-(4-(4-(2- methoxyethyl)piperazin-1-yl)pyridin-2-yl)-5-(pyrimidin-5- yl)thiazolo[5,4-b]pyridin-2- amine449.1  300

407 N-(4-(4-(2- methoxyethyl)piperidin-1-yl)pyridin-2-yl)-5-(5-methyl-1H- pyrazol-4-yl)thiazolo[5,4-b]pyridin-2-amine 450.1  301

408 N⁴-(2-methoxyethyl)-N⁴-methyl- N²-(5-(5-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- yl)pyridine-2,4-diamine 396.1  302

409 N²-(5-(1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2-yl)-N⁴-(2-methoxyethyl)-N⁴- methylpyridine-2,4-diamine 382.0  303

410 (R)-N-(4-(4-(2-methoxyethyl)-2- methylpiperazin-1-yl)pyridin-2-yl)-5-(5-methyl-1H-pyrazol-4- yl)thiazolo[5,4-b]pyridin-2- amine 465.2 304

411 (S)-N-(4-(2-methyl-4- (methylsulfonyl)piperazin-1-yl)pyridin-2-yl)-5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2- amine 482.0 305

412 (S)-5-(5-methyl-1H-pyrazol-4- yl)-N-(4-(2-methyl-4-(methylsulfonyl)piperazin-1- yl)pyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine 485.1  306

413 2-((4-morpholinopyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile337.9  307

414 2-((4-(pyrrolidine-1- carbonyl)pyridin-2-yl)amino)benzo[d]thiazole-6- carbonitrile 349.9  308

415 (2-((5-bromothiazolo[5,4- b]pyridin-2-yl)amino)pyridin-4-yl)(pyrrolidin-1-yl)methanone 403.78 309

416 N-(4-(cyclopentyloxy)pyridin-2- yl)-5-(pyridin-4-yl)thiazolo[5,4-b]pyridin-2-amine 390.0  310

417 N-(4-(cyclopentyloxy)pyridin-2- yl)-5-(5-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridin-2- amine 393.1  311

418 5-ethynyl-N-(4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)thiazolo[5,4-b]pyridin-2- amine 336.0  312

419 N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)-6-methylbenzo[d]thiazol-2-amine 384.02 313

420 2-((4,6-dimethylpyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile281.02 314

421 2-((4-(1,4-dioxa-8- azaspiro[4.5]decan-8-yl)pyridin-2-yl)amino)benzo[d]thiazole-6- carbonitrile 394.0  315

422 2-((4-(4-oxopiperidin-1- yl)pyridin-2- yl)amino)benzo[d]thiazole-6-carbonitrile 349.97 316

423 N-(4-(4-(2- methoxyethyl)piperazin-1- yl)pyridin-2-yl)-[1,3]dioxolo[4′,5′:4,5]benzo[1,2- d]thiazol-6-amine 415.92 317

424 6-isopropyl-N-(4-(4-(2- methoxyethyl)piperazin-1-yl)pyridin-2-yl)benzo[d]thiazol- 2-amine 412.01 318

425 2-((4-(4-hydroxpiperidin-1- yl)pyridin-2-yl)amino)benzo[d]thiazole-6- carbonitrile 351.92 319

426 2-((4-(2-methoxyethoxy)pyridin- 2-yl)amino)benzo[d]thiazole-6-carbonitrile 326.91 320

427 2-((4-isobutoxypyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile324.96 321

428 N-(4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)-5-vinylthiazolo[5,4-b]pyridin-2- amine 322

429 5-ethyl-N-(4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)thiazolo[5,4-b]pyridin-2- amine 323

430 5-(pyridin-4-yl)-N-(4- ((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)thiazolo[5,4- b]pyridin-2-amine 406.1  324

431 N-(4-ethylpyridin-2-yl)-6-(1H- imidazol-4-yl)benzo[d]thiazol-2-amine 321.92 325

432 1-(4-(2-((5-ethynylthiazolo[5,4- b]pyridin-2-yl)amino)pyridin-4-yl)piperazin-1-yl)-2- methoxyethanone 409.0  326

433 4-(2-((5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4- yl)morpholin-3-one 405.1  327

434 2-((4-ethylpyridin-2- yl)amino)benzo[d]thiazole-6- carbonitrile280.95 328

435 1,1-dimethyl-3-(2-((5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4-yl)urea 392.1  329

436 5-(5-methyl-1H-pyrazol-4-yl)-N- (4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyridin-2- yl)thiazolo[5,4-b]pyridin-2- amine 477.1 330

437 Methyl (2-((5-(pyridin-4- yl)thiazolo[5,4-b]pyridin-2-yl)amino)pyridin-4-yl)carbamate 379.1  331

438 2-((4-(hydroxymethyl)pyridin-2- yl)amino)benzo[d]thiazole-6-carbonitrile 283.0  332

439 5-cyclopropyl-N-(4-(pyrrolidin- 1-ylmethyl)pyridin-2-yl)thiazolo[5,4-b]pyridin-2- amine 352.1 

Example 333—Synthesis ofN-(4-ethylpyridin-2-yl)-6-(oxazol-5-yl)benzo[d]thiazol-2-amine (Compound501, Structure 4 in Scheme II, R¹=ethyl, R⁴=5-oxazolyl)

A mixture of 4-ethylpyridin-2-amine (100 mg, 0.821 mmol) andbis(1-benzotriazolyl)methanethione (250 mg, 0.891 mmol) were dissolvedin 5 mL of anhydrous N,N-dimethylacetamide. The solution was stirred atroom temperature for 1 hour. 4-(Oxazol-5-yl)aniline (130 mg, 0.821 mmol)was the added and the solution stirred at 50° C. for an additional hour.Water (15 mL) was then added and the resulting precipitate collected byvacuum filtration and dried under vacuum. The resulting tan powder wasused without further purification. MS calculated for C₁₇H₁₆N₄OS:325.1045; [M+H]⁺, found: 324.89.

1-(4-Ethylpyridin-2-yl)-3-(4-(oxazol-5-yl)phenyl)thiourea (0.27 g, 0.8mmol) was dissolved in 5 mL of acetic acid. Benzyltrimethylammoniumtribromide (320 mg, 0.821 mmol) was then added directly. The mixture wasstirred at 50° C. for 1 hour. The mixture was cooled to 0° C. anddiluted with 15 mL of water. The resulting solution was then made basicthrough addition of solid KOH pellets. The resulting precipitate wascollected by vacuum filtration, washed with water and dried under vacuumto afford the crude product as a tan solid. A portion of the solid waspurified by rp-HPLC affording 0.6 mg ofN-(4-ethylpyridin-2-yl)-6-(oxazol-5-yl)benzo[d]thiazol-2-amine 501 as ayellow solid. MS calculated for C₁₇H₁₄N₄OS: 323.0888; [M+H]+, found:322.93. ¹H-NMR (400 MHz, MeOD) 8.25-8.23 (m, 2H), 8.17 (s, 1H), 7.75 (d,J=8.4, 1H), 7.66 (d, J=8.4, 1H) 7.50 (s, 1H), 6.97 (s, 1H), 6.88 (d,J=8.4, 1H), 2.68 (q, J=7.7, 2H), 1.28 (t, J=7.7, 3H).

Example 334—Synthesis of6-(1H-pyrazol-4-yl)-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-amine(Compound 493, structure 10 in Scheme III, R¹═CH₂—N-pyrrolidinyl,R⁴=4-pyrazolyl)

To a solution of 6-bromoimidazo[1,2-a]pyridin-2-amine (200 mg; 0.94mmol) in dry THF (4 mL) was added NaH (90 mg; 3.76 mmol) in portions at0° C. The reaction mixture was stirred at r.t. for half an hour. Then2-chloro-4-(pyrrolidin-1-ylmethyl)pyridine (222 mg, 1.1 mmol) was added.The mixture was heated to 120° C. for 24 hrs. The mixture was quenchedby addition of H₂O (20 mL) slowly at 0° C., extracted with DCM (30mL×3). The combined organic phases were concentrated under reducedpressure and purified by column chromatography on silica (DCM:MeOH=15:1)to obtain6-bromo-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-amine(110 mg, yield 80%) as a brown solid.

To a solution of6-bromo-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-amine(50 mg, 0.13 mmol) in mixed dioxane/H₂O (2 mL/0.5 mL) was added thepinacol boronate ester (59.2 mg, 0.2 mmol), K₂CO₃ (55.6 mg, 0.4 mmol)and Pd(dppf)Cl₂ (10.8 mg, 0.013 mmol) under nitrogen atmosphere. Themixture reacted under microwave condition at 140° C. for 2 hrs. Aftercooling, the solvent was removed under reduced pressure, and the residuewas purified by prep-TLC to afford6-(1H-pyrazol-4-yl)-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-amine493 (8.5 mg, yield 17.7%). ¹H NMR (400 MHz MeOD) δ 8.93 (s, 1H),8.47-8.45 (d, J=5.2, 1H), 8.12 (s, 2H), 8.06-8.03 (dd, J=9.2, 1H),7.85-7.82 (dd, J=9.6, 1H), 7.14-7.11 (m, 2H), 4.43 (s, 2H), 3.55-3.30(m, 4H), 2.14 (s, 4H).

Examples 335-352

Compounds 484-502 were prepared in a similar fashion as described inExamples 333-334 and their structures, names, and found molecular massion numbers are summarized in Table 2 (Example: E.g.; Compound: Cmpd).

TABLE 2 E.g. Structure Cmpd Name [M + H]⁺ 335

484 2-((4-(hydoxymethyl)pyridin-2- yl)amino)imidazo[1,2-a]pyridine-6-carbonitrile 336

485 (S)-tert-butyl 3-(2-((6- cyanoimidazo[1,2-a]pyridin-2-yl)amino)isonicotinamido)pyrrolidine- 1-carboxylate 448.2 337

486 (S)-2-((6-cyanoimidazo[1,2- a]pyridin-2-yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 348.2 338

487 2-((4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)amino)imidazo[1,2-a]pyridine-6- carbonitrile 319.2 339

488 6-(pyridin-3-yl)-N-(4-(pyrrolidin-1-ylmethyl)pyridin-2-yl)imidazo[1,2- a]pyridin-2-amine 371.1 340

489 1-(4-((2-((6-(pyridin-4-yl)imidazo[1,2-a]pyridin-2-yl)amino)pyridin-4- yl)methyl)piperazin-1-yl)ethanone 428.1341

490 1-(4-((2-((6-(pyridin-3-yl)imidazo[1,2-a]pyridin-2-yl)amino)pyridin-4- yl)methyl)piperazin-1-yl)ethanone 428.1342

491 (2-((6-(pyridin-4-yl)imidazo[1,2- a]pyridin-2-yl)amino)pyridin-4-yl)methanol 318.1 343

492 N-(4-(piperazin-1-ylmethyl)pyridin-2-yl)-6-(pyridin-4-yl)imidazo[1,2- a]pyridin-2-amine 386.1 345

494 1-(4-((2-((6-(1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-2-yl)amino)pyridin-4- yl)methyl)piperazin-1-yl)ethanone 417.7 346

495 N-(4-(piperazin-1-ylmethyl)pyridin-2-yl)-6-(1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-2-amine 375.1 347

496 (2-((6-(1H-pyrazol-4-yl)imidazo[1,2- a]pyridin-2-yl)amino)pyridin-4-yl)methanol 307.1 348

497 N-(4-(4-(methylsulfonyl)piperazin-1- yl)pyridin-2-yl)-6-(pyridin-4-yl)imidazo[1,2-a]pyridin-2-amine 450.1 349

498 2-methoxy-1-(4-(2-((6-(pyridin-4- yl)imidazo[1,2-a]pyridin-2-yl)amino)pyridin-4-yl)piperazin-1- yl)ethanone 444.2 350

499 N-(4-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)-6-(1H-pyrazol-4- yl)imidazo[1,2-a]pyridin-2-amine 439.1351

500 6-(5-methyl-1H-pyrazol-4-yl)-N-(4- (4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyridin- 2-amine 453.1 352

502 (2-((6-(pyridin-3-yl)imidazo[1,2- a]pyridin-2-yl)amino)pyridin-4-yl)methanol 318.0

Examples 353-430

Compounds 503-580 were prepared in a similar fashion as described inExamples 1-2 and 333-334, and their structures and names are summarizedin Table 3 (Example: E.g.; Compound: Cmpd).

TABLE 3 E.g. Structure Cmpd Name 353

503 3-((5-trifluoromethylbenzo[d]thiazol-2-yl)amino)-N-(pyrrolidin-3-yl)benzamide 354

504 3-((6-nitrobenzo[d]thiazol-2-yl)amino)-N- (pyrrolidin-3-yl)benzamide355

505 2-(3-(pyrrolidin-1-ylmethyl)phenylamino)- 6-cyanobenzo[d]thiazole356

506 (R)-2-(benzo[d]thiazol-2-ylamino)-4-(3-hydroxypropylamino)-6-(pyrrolidin-3- ylamino)-1,3,5-triazine 357

507 (R)-2-(benzo[d]thiazol-2-ylamino)-4-(2-hydroxyethylamino)-6-(pyrrolidin-3- ylamino)-1,3,5-triazine 358

508 (R)-2-(benzo[d]thiazol-2-ylamino)-4-methylamino-6-(pyrrolidin-3-ylamino)- 1,3,5-triazine 359

509 2-((6-fluorobenzo[d]thiazol-2-yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 360

510 2-((6-hydroxybenzo[d]thiazol-2-yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 361

511 2-((6-trifluoromethylbenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 362

512 2-((6-trifluoromethoxybenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 363

513 2-((6-methoxybenzo[d]thiazol-2-yl)amino)- 6-methyl-N-(pyrrolidin-3-yl)isonicotinamide 364

514 2-((6-hydroxymethylbenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 365

515 (R)-2-((6-methoxybenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 366

516 (S)-2-((6-phenylbenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 367

517 (S)-2-((6-methylsulfonylbenzo[d]thiazol-2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide 368

518 2-((quinolin-2-yl)amino)-N-(pyrrolidin-3- yl)isonicotinamide 369

519 (S)-2-((6-cyanoquinolin-2-yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 370

520 (R)-2-((6-N-methyl-N-(2- methoxyethyl)benzo[d]thiazol-2-yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 371

521 (R)-2-((6-morpholinobenzo[d]thiazol-2- yl)amino)-N-(pyrrolidin-3-yl)isonicotinamide 372

522 2-((6-(1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)amino)-N-(pyrrolidin-3-yl)-4- pyrimidinecarboxamide 373

523 5-((6-(1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)amino)-N-(pyrrolidin-3-yl)nicotinamide 374

524 2-((6-bromobenzo[d]thiazol-2-yl)amino)-4- (N-methyl-N-(2-methoxyethyl)aminomethyl)pyridine 375

525 2-((6-bromobenzo[d]thiazol-2-yl)amino)-4- (morpholinomethyl)pyridine376

526 2-((6-bromobenzo[d]thiazol-2-yl)amino)-4-(4-methylpiperazinomethyl)pyridine 377

527 2-((6-(3,5-dimethylisoxazol-4- yl)benzo[d]thiazol-2-yl)amino)-4-(pyrrolidin-1-ylmethyl)pyridine 378

528 2-((6-(3-chloropyridin-4-yl)benzo[d]thiazol-2-yl)amino)-4-(pyrrolidin-1- ylmethyl)pyridine 379

529 2-((6-(3-methoxyphenyl)benzo[d]thiazol-2-yl)amino)-4-(pyrrolidin-1-ylmethyl)pyridine 380

530 2-((6-(3,5-dimethylpyrazol-4- yl)benzo[d]thiazol-2-yl)amino)-4-(pyrrolidin-1-ylmethyl)pyridine 381

531 2-((6-(2,2,2-trifluoroethyl)benzo[d]thiazol-2-yl)amino)-4-(pyrrolidin-1- ylmethyl)pyridine 382

532 2-((6-(2,2,2-trifluoroethyl)benzo[d]thiazol-2-yl)amino)-4-(4-methoxyacetylpiperazin- 1-yl)pyridine 383

533 2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4-(1-cyanoacetylpiperidin-4-yl)pyridine 384

534 2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4-(1-cyanomethylpiperidin-4-yl)pyridine 385

535 2-((6-(imidazol-1-yl)benzo[d]thiazol-2-yl)amino)-4-hydroxymethylpyridine 386

536 2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4-(1-(4-methoxyphenyl)acetylpiperidin-4- yl)pyridine 387

537 2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4-(1-(3-cyclopentyl-1-oxopropyl)piperidin-4- yl)pyridine 388

538 2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4-(1-(1-oxopropyl)piperidin-4-yl)pyridine 389

539 2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4-(1-cyclopropylcarbonylpiperidin-4- yl)pyridine 390

540 2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4-(1-trifluoroacetylpiperidin-4-yl)pyridine 391

541 2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4-(1-ethylsulfonylpiperidin-4-yl)pyridine 392

542 2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4-(1-methoxyacetylpiperidin-4-yl)pyridine 393

543 2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4- (piperidin-4-yl)pyridine394

544 2-((6-(pyrazol-1-yl)benzo[d]thiazol-2-yl)amino)-4-(pyrrolidin-1-ylmethyl)pyridine 395

545 2-((6-(3-fluoropyridin-4-yl)benzo[d]thiazol-2-yl)amino)-4-(pyrrolidin-1- ylmethyl)pyridine 396

546 2-((6-(pyrazol-4-yl)benzo[d]thiazol-2- yl)amino)-4-hydroxymethyl-3-fluoropyridine 397

547 2-((6-bromobenzo[d]thiazol-2-yl)amino)-4- hydroxymethylpyridine 398

548 2-((6-bromobenzo[d]thiazol-2-yl)amino)-4- ethylpyridine 399

549 5-((6-cyanobenzo[d]thiazol-2-yl)amino)-3- methylisoxazole 400

550 2-((6-cyanobenzo[d]thiazol-2-yl)amino)-5- methyl-4-phenylthiazole401

551 2-((6-cyanobenzo[d]thiazol-2-yl)amino)-5-(4-methoxyphenyl)-1,3,4-thiadiazole 402

552 2-((6-(oxazol-5-yl)benzo[d]thiazol-2-yl)amino)-4-(4-(2-methoxyethyl)piperazin- 1-yl)pyridine 403

553 2-((6-(2-methyl-1,3,4-oxadiazol-5- yl)benzo[d]thiazol-2-yl)amino)-4-ethylpyridine 404

554 2-(3-hydroxymethylphenyl)amino-6- cyanobenzo[d]thiazole 405

555 2-((6-(1,3,4-oxadiazol-2- yl)benzo[d]thiazol-2-yl)amino)-4-ethylpyridine 406

556 2-((6-(1,3,4-thiadiazol-2- yl)benzo[d]thiazol-2-yl)amino)-4-ethylpyridine 407

557 2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4-(pyrrolidin-1-ylmethyl)pyridine 408

558 2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4-(pyrrolidin-1-ylthiocarbonyl)pyridine 409

559 2-(3,5-dimethoxymethylphenyl)amino-6- cyanobenzo[d]thiazole 410

560 4-((6-(1H-pyrazol-4-yl)benzo[d]thiazol-2-yl)amino)-N-(pyrrolidin-3-yl)-6- pyrimidinecarboxamide 411

561 5-(5-methyl-1H-pyrazol-4-yl)-2-(4- hydroxymethylpyridin-2-ylamino)thiazolo[5,4-b]pyridine 412

562 5-(pyridin-4-yl)-2-(5- isopropyloxymethylisoxazol-3-ylamino)thiazolo[5,4-b]pyridine 413

563 5-(1H-pyrazol-4-yl)-2-(3-(4- methoxyacetylpiperazin-1-ylphenyl)amino)thiazolo[5,4-b]pyridine 414

564 5-ethyl-2-(3-(4-methoxyacetylpiperazin-1-ylphenyl)amino)thiazolo[5,4-b]pyridine 415

565 5-ethyl-2-(4-(1-methoxyacetylpiperidin-4-ylpyridin-2-yl)amino)thiazolo[5,4- b]pyridine 416

566 5-ethyl-2-(4-(pyrrolidon-1-ylpyridin-2-yl)amino)thiazolo[5,4-b]pyridine 417

567 5-(pyridine-4-yl)-2-(4-(3-dimethylamino-3-oxopropyl)pyridin-2-yl)amino)thiazolo[5,4- b]pyridine 418

568 5-(1-methylimidazol-5-yl)-2-(4-(4-methoxyacetylpiperazin-1-ylpyridin-2- yl)amino)thiazolo[5,4-b]pyridine419

569 5-(pyrimidin-4-yl)-2-(4-(4- methoxyacetylpiperazin-1-ylpyridin-2-yl)amino)thiazolo[5,4-b]pyridine 420

570 5-(thiazol-5-yl)-2-(4-(4- methoxyacetylpiperazin-1-ylpyridin-2-yl)amino)thiazolo[5,4-b]pyridine 421

571 5-propyl-2-(4-(4-methoxyacetylpiperazin-1-ylpyridin-2-yl)amino)thiazolo[5,4- b]pyridine 422

572 5-(1H-pyrazol-4-yl)-2-(2-pyrrolidon-1-ylmethylpyridin-4-yl)amino)thiazolo[5,4- b]pyridine 423

573 5-(pyridin-4-yl)-2-(4-(1-methyl-2- oxopiperidin-4-ylpyridin-2-yl)amino)thiazolo[5,4-b]pyridine 424

574 5-(1-methylimidazol-5-yl)-2-(4-(2-dimethylaminocarbonylethyl)pyridin-2- yl)amino)thiazolo[5,4-b]pyridine425

575 5-(pyridine-4-yl)-2-(4-(4- methoxyacetylpiperazin-1-ylpyridin-2-yl)amino)oxazolo[5,4-b]pyridine 426

576 2-((6-cyanobenzo[d]thiazol-2-yl)amino)-4-(1-phenylcarbonylpiperidin-4-yl)pyridine 427

577 6-cyano-2-(4-(4-methoxyacetyl-piperazin-1-yl)pyridin-2-ylamino)imidazo[1,2- a]pyridine 428

578 6-cyano-2-(4-(4-(2- methoxyethyl)piperazin-1-yl)pyridin-2-ylamino)imidazo[1,2-a]pyridine 429

579 6-(1H-pyrazol-4-yl)-2-(4- morpholinopyridin-2-ylamino)imidazo[1,2-a]pyridine 430

580 5-(pyridin-3-yl)-2-(4-(piperazin-1-ylmethylpyridin-2-yl)amino)thiazolo[5,4- b]pyridine

Example 431—Inhibition Assay

The following assay is useful for evaluating test compounds forinhibition of IRAK-1 or IRAK-4 kinase activity. A 96-well polystyrenemicrotiter plates are coated with neutravidin for IRAK-1 or streptavidinfor IRAK-4 (10 mg/mL in PBS, overnight at 4° C.). The coating solutionis removed and in 80 μL/well, a kinase reaction mixture is added (forIRAK-1: 20 mM Tris-HCl, pH 7.5, 10 mM MgCl₂, 2 mM EGTA, 1 mM NaF, 0.5 mMbenzamidine, 1 mM DTT, 3 μM ATP, 1 mM of biotinylated substrate peptidebio-ARFSRFAGSSPSQSSMVAR, sequence derived from IRAK-1; for IRAK-4: 20 mMTris-HCl, pH 7.5, 10 mM MgCl₂, 2 mM EGTA, 1 mM NaF, 0.5 mM benzamidine,1 mM DTT, 10% glycerol, 10 μM ATP, 1 mM of biotinylated substratepeptide bio-RRRVTSPARRS, sequence derived from GFAP).

At 10 μL/well in DMSO test compounds are added covering a finalconcentration range from 1 nM to 30 mM. Recombinant, full-length IRAK-1or IRAK-4 enzyme (baculovirus expression system) is added in 10 μLbuffer containing 20 mM Tris-HCl, pH 7.5, 2 mM EGTA, 0.5 mM benzamidine,1 mM DTT, 10 mM MgCl₂, and glycerol 10% (IRAK-4 only) to initiate thekinase reaction. The reaction mixture is incubated at room temperaturefor 60 min on a shaker. During this incubation the substrate peptide isbeing phosphorylated by the kinase and gets captured onto the surface ofthe wells by neutravidin or streptavidin, respectively. The plate iswashed 3× with 150 μL distilled water to terminate the reaction andremove components of the reaction mixture. A conventionalchemiluminescent ELISA detection technique is initiated by adding 100μL/well primary antibody (monoclonal antibody YC10, generated torecognize the phosphorylated epitope in the substrate peptide; use at1:20,000 dilution for IRAK-1 and 1:10,000 dilution for IRAK-4) premixedwith horseradish peroxidase (HRP) conjugated anti-mouse secondaryantibody (commercially available from several sources; use at 1:10,000dilution) in PBS containing 2% BSA. The solution is incubated at roomtemperature for 40 min on a shaker, then washed 3× with 150 μL of water.100 μL 10× diluted SuperSignal HRP substrate (from Pierce) is added andafter 5 min incubation the chemiluminescent signal is captured by aLabsystems LuminoSkan luminometer. The point of 50% inhibition of IRAK-1or IRAK-4 enzyme activity (IC₅₀) is determined. Table 4 summarizes dataobtained using an assay substantially similar to the foregoing method(Compound: Cmpd).

TABLE 4 Cmpd EC₅₀ Cmpd EC₅₀ Cmpd EC₅₀ Cmpd EC₅₀ 101 A 110 A 120 A 130 A137 A 150 A 160 A 170 A 180 A 190 A 200 A 210 A 220 A 230 A 240 A 250 A260 A 270 A 280 A 290 A 300 A 310 A 320 A 330 A 340 A 350 A 360 A 370 A380 A 390 A 401 A 410 A 420 A 430 A 439 A 484 B 490 A 500 A 510 B 521 B530 B 540 A 553 B 560 B 570 A 580 B

It is to be understood that both the foregoing general description anddetailed description are exemplary and explanatory only and are notrestrictive of the embodiments claimed. In this application, the use ofthe singular includes the plural unless specifically stated otherwise.In this application, the use of “or” means “and/or” unless statedotherwise. Furthermore, use of the term “including” as well as otherforms, such as “includes,” and “included,” is not limiting. The term“comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

All references cited herein, including but not limited to published andunpublished applications, patents, and literature references, areincorporated herein by reference in their entirety and are hereby made apart of this specification. To the extent publications and patents orpatent applications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention.

What is claimed is:
 1. A compound having a structure of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein: X is N or CR⁵′,wherein R⁵′ is selected from hydrogen, halogen, OR⁶, an optionallysubstituted C₁-C₆ alkyl, an optionally substituted C₁-C₆ haloalkyl, anoptionally substituted C₁-C₆ alkenyl, and an optionally substitutedC₁-C₆ alkynyl; R¹ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸,CH₂OR⁶, CH₂NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionallysubstituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆ alkenyl, anoptionally substituted C₁-C₆ alkynyl, CO₂R⁶, CONR⁷R⁸, SO₃R⁶, andSO₂NR⁷R⁸; R² and R³ are independently selected from hydrogen, halogen,OR⁶, NR⁷R⁸, an optionally substituted C₁-C₆ alkyl, an optionallysubstituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆ alkenyl,and an optionally substituted C₁-C₆ alkynyl; R⁴ is selected fromhalogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substitutednon-aromatic ring, an optionally substituted carbocycle, an optionallysubstituted C₁-C₆ alkyl, an optionally substituted C₁-C₆ haloalkyl, anoptionally substituted C₁-C₆ alkenyl, an optionally substituted C₁-C₆alkynyl, CO₂R⁶, SO₃R⁶, SO₂R⁶ and SO₂NR⁷R⁸; R⁵ is selected from hydrogen,halogen, OR⁶, an optionally substituted C₁-C₆ alkyl, an optionallysubstituted C₁-C₆ haloalkyl, an optionally substituted C₁-C₆ alkenyl,and an optionally substituted C₁-C₆ alkynyl; or R⁴ and R⁵ are linked toform an optionally substituted non-aromatic ring; each R⁶ isindependently selected from an optionally substituted aryl, anoptionally substituted heteroaryl, and an optionally substitutednon-aromatic ring, each optionally fused with a substituted aryl or asubstituted heteroaryl, hydrogen, an optionally substituted C₁-C₁₀alkyl, and an optionally substituted C₁-C₁₀ haloalkyl; each R⁷ and R⁸ isindependently selected from an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substitutednon-aromatic ring, each optionally fused with a substituted aryl or asubstituted heteroaryl, hydrogen, an optionally substituted C₁-C₁₀alkyl, an optionally substituted C₁-C₁₀ haloalkyl, an optionallysubstituted C₁-C₁₀ alkenyl, and an optionally substituted C₁-C₁₀alkynyl, or R⁷ and R⁸ are linked to form an optionally substitutednon-aromatic ring; each heteroaryl is an aromatic 5 to 8 membered ring,or a benzo- or a pyrido-fused derivative thereof, wherein up to 4 atomsforming the aromatic ring is a heteroatom selected from oxygen, sulfur,nitrogen; each non-aromatic ring is a covalently closed 3 to 9 memberedring that does not have a delocalized π-electron system in its principleor predominant tautomer, and the atoms that form the ring include atleast one carbon atom and can optionally include up to four heteroatomsselected from oxygen, sulfur, nitrogen, and phosphorus, and canoptionally include one or more C(═O) or C(═S) groups as part of thering; each carbocycle is a covalently closed C₃-C₉ ring, wherein each ofthe atoms that forms the ring is a carbon atom; each optionallysubstituted group is either unsubstituted or substituted with one ormore groups independently selected from alkyl, alkenyl, alkynyl,haloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic ring, hydroxy,alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, —C(═O)R,—C(═S)R, —OC(═O)—NR, —NHC(═O)OR, —OC(═S)—NR, —NHC(═S)COR, —C(═O)—NR₂,—NHC(═O)CR, —S(═O)₂NR, —NHS(═O)₂R, —C(═O)OR, —OC(═O)R isocyanato,thiocyanato, isothiocyanato, nitro, silyl, —S(═O)₂CX′₃, ═O, ═S, andamino; X′ is halo, and R is alkyl, cycloalkyl, aryl, heteroaryl bondedthrough a ring carbon, and non-aromatic ring bonded through a ringcarbon.
 2. The compound of claim 1, wherein X is N.
 3. The compound ofclaim 1, wherein R¹ is selected from NR⁷R⁸, CH₂OR⁶, CH₂NR⁷R⁸, anoptionally substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆haloalkyl, an optionally substituted C₁-C₆ alkenyl, an optionallysubstituted C₁-C₆ alkynyl, CO₂R⁶, CONR⁷R⁸, SO₃R⁶, and SO₂NR⁷R⁸.
 4. Thecompound of claim 1, wherein R¹ is selected from NR⁷R⁸, CH₂NR⁷R⁸, or anoptionally substituted C₁-C₆ alkyl.
 5. The compound of claim 1, whereinR¹ is selected from NR⁷R⁸, or CH₂NR⁷R⁸.
 6. The compound of claim 1,wherein R⁴ is selected from an optionally substituted heteroarylselected from C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, and anoptionally substituted heteroaryl selected from pyridine, pyrazole,pyridazine, pyrimidine, wherein the heteroaryl is optionally substitutedwith 1-2 substituents selected from C₁-C₆ alkyl and CN.
 7. The compoundof claim 1, wherein R⁴ is selected from cyano, triazolyl, oxazolyl,isoxazolyl, imidazoyl, pyridyl, pyrazolyl, pyrimidinyl, pyridazinyl, andC₁-C₆ alkyl.
 8. The compound of claim 1, wherein R⁴ is selected frompyridyl, pyrazolyl, pyrimidinyl, and pyridazinyl.
 9. The compound ofclaim 1, wherein R⁴ is selected from pyridyl and pyrazolyl.
 10. Thecompound of claim 1, wherein R⁴ is pyrazolyl.
 11. The compound of claim1, wherein R² is H.
 12. The compound of claim 1, wherein R³ is H. 13.The compound of claim 1, wherein R⁵ is H.
 14. The compound of claim 1,wherein the compound is selected from the group consisting of:

or a pharmaceutical salt thereof.
 15. A pharmaceutical compositioncomprising the compound of claim 1 and a pharmaceutically acceptablecarrier.